Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia

ABSTRACT

A compound having the general structure of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, are useful in treating diseases, disorders, or conditions such as metabolic syndrome and dyslipidemia.

PRIORITY INFORMATION

This application claims the benefit of U.S. Provisional Application No.60/760,555, filed Jan. 20, 2006, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to nicotinic acid receptor agonistcompounds useful for treating metabolic syndrome, dyslipidemia,cardiovascular diseases, disorders of the peripheral and central nervoussystem, hematological diseases, cancer, inflammation, respiratorydiseases, gastroenterological diseases, diabetes, and non-alcoholicfatty liver disease; pharmaceutical compositions comprising suchcompounds; pharmaceutical compositions comprising nicotinic acidreceptor agonist compounds in combination with other therapeutic agents;and methods of treatment using the compounds and compositions to treatconditions such as metabolic syndrome, dyslipidemia, cardiovasculardiseases, disorders of the peripheral and central nervous system,hematological diseases, cancer, inflammation, respiratory diseases,gastroenterological diseases, diabetes, hepatic steatosis andnon-alcoholic fatty liver disease.

BACKGROUND OF THE INVENTION

Nicotinic acid has been used to treat metabolic syndrome anddyslipidemia. However, nicotinic acid has undesirable side effects suchas flushing and diarrhea. It is therefore desirable to provide improvednicotinic acid receptor agonists with improved efficacy at treatingmetabolic syndrome and dyslipidemia, yet without the undesirable sideeffects. The compounds of the present invention provide such improvednicotinic acid receptor agonists.

M. Ridi, Gazzetta Chim. Ital. (1950) vol. 80, p. 121 and M. Ridi,Gazzetta Chim. Ital. (1952) vol. 82, p. 23 disclose syntheses ofbarbituric acid derivatives. FR 2563223 discloses nucleoside analogs. T.Paterson et al., J. Chem. Soc., Perkins Trans. 1 (1972), vol. 8, pp.1041-1050 discloses the synthesis of 8-substitutedpyrido[2,3-d]pyrimidines. S. Rao, Indian J. Chem. (1974), 12(10), pp.1028-1030 discloses the synthesis of pyrano[2,3-d]pyrimidines. M. Skof,Heterocycles, (1999), 51(5), pp. 1051-1058 discloses one steptransformations of(S)-1-benzoyl-3-[(E)-dimethylaminomethylidene]-5-methoxycarbonyl-pyrrolidin-2-oneinto quinolizinyl- and 2H-2-pyranonyl-substituted alanine derivatives.R. Toplak J. Heterocyclic Chem. (1999), 36(1), pp. 225-235 discloses thesynthesis of pyran-2-ones. However, the compounds of the abovereferences differ from those of the present invention. WO 2004/110368describes combination therapies for the treatment of hypertensioncomprising the combination of an anti-obesity agent and ananti-hypertensive agent. However, WO 2004/110368 fails to describenicotinic acid receptor agonists, or combinations of one or morenicotinic acid receptor agonists with a second therapeutic agent.

WO 2005/000217 describes combination therapies for the treatment ofdyslipidemia comprising the administration of a combination of ananti-obesity agent and an anti-dyslipidemic agent. However, WO2005/000217 fails to describe nicotinic acid receptor agonists, orcombinations of one or more nicotinic acid receptor agonists with asecond therapeutic agent.

WO 2004/110375 describes combination therapies for the treatment ofdiabetes comprising the administration of a combination of ananti-obesity agent and an anti-diabetic agent. However, WO 2004/110375fails to describe nicotinic acid receptor agonists, or combinations ofone or more nicotinic acid receptor agonists with a second therapeuticagent.

US 2004/0122033 describes combination therapies for the treatment ofobesity comprising the administration of a combination of an appetitesuppressant and/or metabolic rate enhancers and/or nutrient absorptioninhibitors. However, US 2004/0122033 fails to describe nicotinic acidreceptor agonists, or combinations of one or more nicotinic acidreceptor agonists with a second therapeutic agent. US 2004/0229844describes combination therapies for treating atherosclerosis comprisingthe administration of a combination of nicotinic acid or anothernicotinic acid receptor agonist and a DP receptor antagonist. However,the nicotinic acid agonists of US 2004/0229844 are quite different fromthose of the present invention. WO2005/077950 describes xanthinederivatives which are agonists of the nicotinic acid receptor HM74A.However, the xanthine derivatives of WO2005/077950 are quite differentfrom the compounds of the present invention.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, esters, and tautomersthereof, wherein

-   R¹ is selected from the group consisting of H, R⁴, haloalkyl,    -alkylene-R⁴, -alkylene-R⁵, -alkylene-R⁶, alkenyl, alkynyl, and    -alkylene-O-alkyl;-   R² is selected from the group consisting of R⁷, alkyl, haloalkyl,    -alkylene-R⁵, R⁴, R⁵, R⁶, R⁷ and -alkylene-O—R⁸;-   R³ is selected from the group consisting of alkyl, haloalkyl,    -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷; or-   R² and R³ together with the carbon atom to which they are both    attached form a cycloalkyl or heterocycloalkyl ring, wherein said    cycloalkyl or heterocycloalkyl ring is unsubstituted or    independently substituted with one or more X⁵ groups, or wherein    said cycloalkyl ring can form a spirocyclic compound with a second    cycloalkyl ring or with a heterocycloalkyl ring, wherein the second    cycloalkyl ring or the heterocycloalkyl ring is unsubstituted or    independently substituted with one or more X⁵ groups;-   R⁴ is unsubstituted cycloalkyl or cycloalkyl substituted with one or    more X¹ groups;-   R⁵ is unsubstituted aryl and aryl substituted with one or more X²    groups;-   R⁶ is selected from the group consisting of unsubstituted heteroaryl    and heteroaryl substituted with one or more X³ groups;-   R⁷ is unsubstituted heterocycloalkyl and heterocycloalkyl    substituted with one or more X⁴ groups;-   R⁸ is selected from the group consisting of H, alkyl, R⁴, R⁵, R⁶,    R⁷, —C(O)-alkyl, —C(O)—R⁵-   each R⁹ is independently selected from the group consisting of H,    alkyl, R⁴, R⁵, R⁶, and R⁷;-   R¹⁰ is selected from the group consisting of R⁹, —C(O)-alkyl, and    —C(O)—R⁵;-   each R¹¹ is independently alkyl or phenyl;-   Y is —O— or —N(R¹⁰)—;-   each X¹ is independently selected from the group consisting of    halogen, alkyl, —O-alkyl, —OH, haloalkyl, aryl, and alkyne;-   each X² is independently selected from the group consisting of    halogen, alkyl, —O-alkyl, —OH, haloalkyl, aryl, and alkyne;-   each X³ is independently selected from the group consisting of    halogen, alkyl, and N-oxide;-   each X⁴ is independently selected form the group consisting of    alkyl, R⁵, —C(O)-alkyl, —C(O)—R⁵, —C(O)—O-alkyl, -alkylene-R⁵, R⁴,    and —S(O₂)-alkyl; and-   each X⁵ is independently selected from the group consisting of    alkyl, -aryl, —CN, halo, haloalkyl, —O-alkyl, -alkylene-R⁵,    —O—Si(R¹¹)₃, a fused aryl ring, —C(O)-alkyl, a fused heteroaryl    ring, —C(O)—O-alkyl, —C(O)—R⁵, —S(O₂)-alkyl, —C(O)—N(R⁹)₂, R⁵, R⁶,    —C(O)—R⁴, —C(O)—O—R⁴, —S(O₂)—R⁴, —S(O₂)-alkylene-R⁴,    —S(O₂)-alkylene-R⁵, —N(R⁹)—C(O)—O-alkyl, —N(R⁹)—C(O)—O—R⁴,    —N(R⁹)—C(O)—N(R⁹)₂ and —N(R⁹)₂;    -   wherein said fused aryl ring of X⁵ is unsubstituted or        independently substituted with one or more substitutent selected        from -alkylene-R⁷ or X², and said fused heteroaryl ring of X⁵ is        unsubstituted or substituted with one or more X³ groups.

In another embodiment, the present invention is directed to apharmaceutical composition comprising a therapeutically effective amountof at least one compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, and at least onepharmaceutically acceptable carrier.

In another embodiment, the present invention is directed to a method oftreating a disease or disorder in a patient, such as metabolic syndrome,dyslipidemia, cardiovascular diseases, disorders of the peripheral andcentral nervous system, hematological diseases, cancer, inflammation,respiratory diseases, gastroenterological diseases, diabetes, andnon-alcoholic fatty liver disease. The method comprises administering tothe patient an effective amount of at least one compound of Formula (I),or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.

In another embodiment, the present invention is directed to a method oftreating a disease or disorder in a patient, such as metabolic syndrome,dyslipidemia, cardiovascular diseases, disorders of the peripheral andcentral nervous system, hematological diseases, cancer, inflammation,respiratory diseases, gastroenterological diseases, diabetes, hepaticsteatosis, and non-alcoholic fatty liver disease. The method comprisesadministering to the patient an effective amount of at least onecompound of Formula (I), or a pharmaceutically acceptable salt, solvate,ester, or tautomer thereof, in combination with at least one additionalactive ingredient selected from the group consisting ofhydroxy-substituted azetidinone compounds, substituted β-lactamcompounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetaseinhibitors, squalene synthesis inhibitors, squalene epoxidaseinhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives,bile acid sequestrants, inorganic cholesterol sequestrants,AcylCoA:Cholesterol O-acyltransferase inhibitors, cholesteryl estertransfer protein inhibitors, fish oils containing Omega 3 fatty acids,natural water soluble fibers, plant stanols and/or fatty acid esters ofplant stanols, low-density lipoprotein receptor activators,anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptormodulators, LXR receptor agonists, lipoprotein synthesis inhibitors,renin angiotensin inhibitors, microsomal triglyceride transport proteininhibitors, bile acid reabsorption inhibitors, PPAR δ agonists,triglyceride synthesis inhibitors, squalene epoxidase inhibitors, lowdensity lipoprotein receptor inducers, platelet aggregation inhibitors,5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacinreceptor agonists, 5HT transporter inhibitors, NE transporterinhibitors, CB1 antagonists/inverse agonists, ghrelin antagonists, H3antagonists/inverse agonists, MCH1R antagonists, MCH2Ragonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists,NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators,leptin derivatives, opioid antagonists, orexin receptor antagonists,BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTFagonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptakeinhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine,topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists,ACC2 inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FASinhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1activators, UCP-2 activators, UCP-3 activators, acyl-estrogens,glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1inhibitors, lipase inhibitors, fatty acid transporter inhibitors,dicarboxylate transporter inhibitors, glucose transporter inhibitors,phosphate transporter inhibitors, antidiabetic agents, anti-hypertensiveagents, anti-dyslipidemic agents, DP receptor antagonists,apolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists,melanocyte-stimulating hormone receptor analogs, melanin concentratinghormone antagonists, leptons, galanin receptor antagonists, bombesinagonists, neuropeptide-Y antagonists, thyromimetic agents,dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortinbinding protein antagonists, glucagons-like peptide-1 receptor agonists,human agouti-related proteins (AGRP), neuromedin U receptor agonists,noradrenergic anorectic agents, appetite suppressants, hormone sensitivelipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apoA1 milano reverse cholesterol transport inhibitors, fatty acid bindingprotein inhibitors (FABP), and fatty acid transporter protein inhibitors(FATP).

DETAILED DESCRIPTION OF THE INVENTION

The nicotinic acid receptor agonist compounds of the present inventionare useful for treating conditions such as metabolic syndrome,dyslipidemia, cardiovascular diseases, disorders of the peripheral andcentral nervous system, hematological diseases, cancer, inflammation,respiratory diseases, gastroenterological diseases, diabetes, hepaticsteatosis, and non-alcoholic fatty liver disease. One or more compoundsof the present invention can be administered alone or in combinationwith one or more other therapeutic agents as described herein.

In a first embodiment, the present invention is directed to a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, ester,or tautomer thereof, as described herein.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,

-   R¹ is selected from the group consisting of H, R⁴, (C₁-C₆)haloalkyl,    —(C₁-C₆)alkylene-R⁴, —(C₁-C₆)alkylene-R⁵, —(C₁-C₆)alkylene-R⁶,    (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, and —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl;-   R² is selected from the group consisting of R⁷, (C₁-C₆)alkyl,    (C₁-C₆)haloalkyl, —(C₁-C₆-)alkylene-R⁵, R⁴, R⁵, R⁶, R⁷ and    —(C₁-C₆)alkylene-O—R⁸;-   R³ is selected from the group consisting of (C₁-C₆)alkyl,    (C₁-C₆)haloalkyl, —(C₁-C₆-)alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷; or-   R² and R³ together with the carbon atom to which they are both    attached form a (C₃-C₁₀)cycloalkyl or (C₂-C₁₀)heterocycloalkyl ring,    wherein said (C₃-C₁₀)cycloalkyl or (C₂-C₁₀)heterocycloalkyl ring is    unsubstituted or substituted with one or more X⁵ groups.-   R⁴ is unsubstituted (C₃-C₁₀)cycloalkyl or (C₃-C₁₀)cycloalkyl    substituted with one or more X¹ groups;-   R⁵ is unsubstituted (C₆-C₁₄)aryl and (C₆-C₁₄)aryl substituted with    one or more X² groups;-   R⁶ is selected from the group consisting of unsubstituted    (C₂-C₁₀)heteroaryl and (C₂-C₁₀)heteroaryl substituted with one or    more X³ groups;-   R⁷ is unsubstituted (C₂-C₁₀)heterocycloalkyl and    (C₂-C₁₀)heterocycloalkyl substituted with one or more X⁴ groups;-   R⁸ is selected from the group consisting of H, (C₁-C₆)alkyl, R⁴, R⁵,    R⁶, R⁷, —C(O)—(C₁-C₆) alkyl, —C(O)—R⁵-   each R⁹ is independently selected from the group consisting of H,    (C₁-C₆)alkyl, R⁴, R⁵, R⁶, and R⁷;-   R¹⁰ is selected from the group consisting of R⁹, —C(O)—(C₁-C₆)alkyl,    and —C(O)—R⁵;-   Y is —O— or —N(R¹⁰)—;-   each X¹ is independently selected from the group consisting of    halogen, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —OH, (C₁-C₆)haloalkyl,    (C₆-C₁₄)aryl, and (C₁-C₆)alkyne;-   each X² is independently selected from the group consisting of    halogen, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —OH, (C₁-C₆)haloalkyl,    (C₆-C₁₄)aryl, and (C₁-C₆)alkyne;-   each X³ is independently selected from the group consisting of    halogen, (C₁-C₆)alkyl, and N-oxide;-   each X⁴ is independently selected form the group consisting of    (C₁-C₆)alkyl, R⁵, —C(O)—(C₁-C₆)alkyl, —C(O)—R⁵,    —C(O)—O—(C₁-C₆)alkyl, —(C₁-C₆-)alkylene-R⁵, R⁴, and    —S(O₂)—(C₁-C₆)alkyl; and-   each X⁵ is independently selected from the group consisting of    (C₁-C₆)alkyl, a fused (C₆-C₁₄)aryl ring, —C(O)—(C₁-C₆)alkyl, a fused    (C₂-C₁₀)heteroaryl ring, —C(O)—O—(C₁-C₆)alkyl, —C(O)—R⁵,    —S(O₂)—(C₁-C₆)alkyl, —C(O)—N(R⁹)₂, R⁵, R⁶, —C(O)—R⁴, —C(O)—O—R⁴,    —S(O₂)—R⁴, —S(O₂)—(C₁-C₆)alkylene-R⁴, —S(O₂)—(C₁-C₆-)alkylene-R⁵,    —N(R⁹)—C(O)—O—(C₁-C₆)alkyl, —N(R⁹)—C(O)—O—R⁴, —N(R⁹)—C(O)—N(R⁹)₂ and    —N(R⁹)₂;    -   wherein said fused (C₆-C₁₄)aryl ring of X⁵ is unsubstituted or        independently substituted with one or more substitutent selected        from —(C₁-C₆)alkylene-R⁷ or X², and said fused        (C₂-C₁₀)heteroaryl ring of X⁵ is unsubstituted or substituted        with one or more X³ groups.

In one embodiment, R¹ is alkyl.

In another embodiment, R¹ is -alkylene-cycloalkyl.

In another embodiment, R¹ is haloalkyl.

In still another embodiment, R¹ is -alkylene-O-alkyl.

In yet another embodiment, R¹ is —(CH₂)₃CF₃.

In another embodiment, R¹ is n-butyl, n-pentyl, n-hexyl, isopentyl,isohexyl or neoheptyl.

In a further embodiment, R¹ is —(CH₂)₂-cyclopropyl, —(CH₂)₃-cyclopropyl,—(CH₂)₄-cyclopropyl, —(C H₂)₂-cyclobutyl, —(CH₂)₂-cyclopentyl,—CH₂-cyclohexyl, —(CH₂)₂-cyclohexyl or

In another embodiment, R¹ is —(CH₂)₃—O—(CH₂)₂CH₃.

In one embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a monocyclic cycloalkyl group.

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a bicyclic cycloalkyl group.

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a monocyclic hetercycloalkyl group.

In still another embodiment, R², R³ and the carbon atom to which theyare both attached, combined to form a bicyclic hetercycloalkyl group.

In yet another embodiment, R², R³ and the carbon atom to which they areboth attached, combined to form a cyclopentyl or cyclohexyl group.

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a decahydronaphtyl,1,2,3,4-tetrahydronaphthyl, bicyclo[2.2.2]octyl or spiro[2.5]octylgroup.

In a further embodiment, R², R³ and the carbon atom to which they areboth attached, combined to form a piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl or tetrahydrothiopyranyl-1,1,-dioxide group

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a 8-aza-bicyclo[3.2.1]octyl,1,4-dioxa-spiro[4.5]decanyl, 4,5,6,7-tetrahydro-benzo[b]thiophenyl,5,6,7,8-tetrahydroquinolinyl or 1,3-diaza-spiro[4.5]decanyl-2,4,-dionegroup.

In one embodiment, R¹ is alkyl, and R², R³ and the carbon atom to whichthey are both attached, combined to form a monocyclic cycloalkyl group.

In another embodiment, R¹ is alkyl, and R², R³ and the carbon atom towhich they are both attached, combined to form a bicyclic cycloalkylgroup.

In another embodiment, R¹ is alkyl, and R², R³ and the carbon atom towhich they are both attached, combined to form a monocyclicheterocycloalkyl group.

In still another embodiment, R¹ is alkyl, and R², R³ and the carbon atomto which they are both attached, combined to form a bicyclicheterocycloalkyl group.

In one embodiment, R¹ is haloalkyl, and R², R³ and the carbon atom towhich they are both attached, combined to form a monocyclic cycloalkylgroup.

In another embodiment, R¹ is haloalkyl, and R², R³ and the carbon atomto which they are both attached, combined to form a bicyclic cycloalkylgroup.

In another embodiment, R¹ is haloalkyl, and R², R³ and the carbon atomto which they are both attached, combined to form a monocyclicheterocycloalkyl group.

In still another embodiment, R¹ is haloalkyl, and R², R³ and the carbonatom to which they are both attached, combined to form a bicyclicheterocycloalkyl group.

In one embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ and the carbonatom to which they are both attached, combined to form a monocycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form a bicycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form amonocyclic heterocycloalkyl group.

In still another embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ andthe carbon atom to which they are both attached, combined to form abicyclic heterocycloalkyl group.

In one embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and the carbonatom to which they are both attached, combined to form a monocycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form a bicycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form amonocyclic heterocycloalkyl group.

In still another embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form a bicyclicheterocycloalkyl group.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁴.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁴ and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁴ and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁵.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁵ and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁵ and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁶.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁶ and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁶ and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is R¹ is alkyl; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is R¹ is alkyl; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; R² and R³ are each independently selected from the groupconsisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷; and Yis —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is haloalkyl; and R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is haloalkyl; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is haloalkyl; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁴; and R² and R³ are each independently selected fromthe group consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, andR⁷.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁴; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁴; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁵; and R² and R³ are each independently selected fromthe group consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, andR⁷.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁵; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁵; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁶; and R² and R³ are each independently selected fromthe group consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, andR⁷.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁶; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is -alkylene-R⁶; R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷;and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; and R² and R³ together with the carbon atom to which theyare both attached form a cycloalkyl ring, wherein said cycloalkyl ringis unsubstituted or substituted with one or more X¹ groups.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; R² and R³ together with the carbon atom to which they areboth attached form a cycloalkyl ring, wherein said cycloalkyl ring isunsubstituted or substituted with one or more X¹ groups; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; R² and R³ together with the carbon atom to which they areboth attached form a cycloalkyl ring, wherein said cycloalkyl ring isunsubstituted or substituted with one or more X¹ groups; and Y is—N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; and R² and R³ together with the carbon atom to which theyare both attached form a heterocycloalkyl ring, wherein saidheterocycloalkyl ring is unsubstituted or substituted with one or moreX⁴ groups.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; R² and R³ together with the carbon atom to which they areboth attached form a heterocycloalkyl ring, wherein saidheterocycloalkyl ring is unsubstituted or substituted with one or moreX⁴ groups; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is alkyl; R² and R³ together with the carbon atom to which they areboth attached form a heterocycloalkyl ring, wherein saidheterocycloalkyl ring is unsubstituted or substituted with one or moreX⁴ groups; and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, or—CH₂CH₂CH₂-cyclopropyl; R² and R³ are each independently selected fromthe group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl, piperazinyl,piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl;and R⁵ is phenyl.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, or—CH₂CH₂CH₂-cyclopropyl; R² and R³ are each independently selected fromthe group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl, piperazinyl,piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl;and R⁵ is phenyl; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, or—CH₂CH₂CH₂-cyclopropyl; R² and R³ are each independently selected fromthe group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl, piperazinyl,piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl;and R⁵ is phenyl; and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, or —CH₂CH₂CH(CH₃)₂; R²and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl group selected from:

each of said cycloalkyl or heterocycloalkyl rings is unsubstituted orsubstituted with one or more X⁴ groups.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, or —CH₂CH₂CH(CH₃)₂; R²and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl group selected from:

each of said cycloalkyl or heterocycloalkyl rings is unsubstituted orsubstituted with one or more X⁴ groups; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, or —CH₂CH₂CH(CH₃)₂; R²and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl selected from the group consistingof:

each of said cycloalkyl or heterocycloalkyl rings is unsubstituted orsubstituted with one or more X⁴ groups; and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is R¹ is —CH₂CH₂CH₂CF₃, —CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or—CH₂—R⁶.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is R¹ is —CH₂CH₂CH₂CF₃, —CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or—CH₂—R⁶; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃, —CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or —CH₂—R⁶; andY is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃, —CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or —CH₂—R⁶; R²and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl group selected from:

each of said cycloalkyl or heterocycloalkyl rings is unsubstituted orsubstituted with one or more X⁴ groups.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃, —CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or —CH₂—R⁶; R²and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl group selected from:

each of said cycloalkyl or heterocycloalkyl rings is unsubstituted orsubstituted with one or more X⁴ groups; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃, —CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or —CH₂—R⁶; R²and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl group selected from:

each of said cycloalkyl or heterocycloalkyl rings is unsubstituted orsubstituted with one or more X⁴ groups; and Y is —N(R¹⁰)—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃ or —CH₂CH₂—R⁴; and R² and R³ are each independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl,piperazinyl, piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, andthiazolyl.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃ or —CH₂CH₂—R⁴; R² and R³ are each independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl,piperazinyl, piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, andthiazolyl; and Y is —O—.

In another embodiment of the compounds of Formula (I), or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,R¹ is —CH₂CH₂CH₂CF₃ or —CH₂CH₂—R⁴; R² and R³ are each independentlyselected from the group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl,piperazinyl, piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, andthiazolyl; and Y is —N(R¹⁰)—.

In yet another embodiment, the present invention is directed to acomposition comprising compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, in combinationwith at least one additional therapeutic agent selected from the groupconsisting of hydroxy-substituted azetidinone compounds, substitutedβ-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoAsynthetase inhibitors, squalene synthesis inhibitors, squalene epoxidaseinhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives,bile acid sequestrants, inorganic cholesterol sequestrants,AcylCoA:Cholesterol O-acyltransferaseinhibitors, cholesteryl estertransfer protein inhibitors, fish oils containing Omega 3 fatty acids,natural water soluble fibers, plant stanols and/or fatty acid esters ofplant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXRreceptor modulators, LXR receptor agonists, lipoprotein synthesisinhibitors, renin angiotensin inhibitors, microsomal triglyceridetransport inhibitors, bile acid reabsorption inhibitors, PPAR δagonists, triglyceride synthesis inhibitors, squalene epoxidaseinhibitors, low density lipoprotein receptor inducers or activators,platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partialagonists, niacin or niacin receptor agonists, 5HT transporterinhibitors, NE transporter inhibitors, CB₁ antagonists/inverse agonists,ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1R antagonists,MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptinagonists/modulators, leptin derivatives, opioid antagonists, orexinreceptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTFderivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists,monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1agonists, phentermine, topiramate, phytopharm compound 57, ghrelinantibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroidhormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11βHSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acidtransporter inhibitors, dicarboxylate transporter inhibitors, glucosetransporter inhibitors, phosphate transporter inhibitors, antidiabeticagents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptorantagonists, apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamineagonists, melanocyte-stimulating hormone receptor analogs, melaninconcentrating hormone antagonists, leptons, galanin receptorantagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone, analogs of dehydroepiandrosterone,urocortin binding protein antagonists, glucagons-like peptide-1 receptoragonists, human agouti-related proteins (AGRP), neuromedin U receptoragonists, noradrenergic anorectic agents, appetite suppressants, hormonesensitive lipase antagonists, MSH-receptor analogs, α-glucosidaseinhibitors, apo A1 milano reverse cholesterol transport inhibitors,fatty acid binding protein inhibitors (FABP), and fatty acid transporterprotein inhibitors (FATP).

In yet another embodiment, the present invention is directed to acomposition comprising compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, in combinationwith a HMG CoA synthetase inhibitor selected from the group consistingof lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin,cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

In yet another embodiment, the present invention is directed to acomposition comprising compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, in combinationwith simvastatin.

In yet another embodiment, the present invention is directed to acomposition comprising compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, in combinationwith a cholesteryl ester transfer protein inhibitor.

In yet another embodiment, the present invention is directed to acomposition comprising compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, in combinationwith torcetrapib.

In still another embodiment, the present invention is directed to amethod of treating a disease, disorder, or condition with a compound ofFormula (I), or a composition comprising a compound of Formula (I)together with at least one addition therapeutic agent, for example oneof the therapeutic agents, or classes of therapeutic agents describedherein. The diseases, disorders, or conditions which may be treated withthe compound or compositions of the present invention include metabolicsyndrome, dyslipidemia, cardiovascular diseases, disorders of theperipheral and central nervous system, hematological diseases, cancer,inflammation, respiratory diseases, gastroenterological diseases,diabetes, and non-alcoholic fatty liver disease.

R¹ is selected from the group consisting of H, R⁴, haloalkyl,-alkylene-R⁴, -alkylene-R⁵, -alkylene-R⁶, alkenyl, alkynyl, and-alkylene-O-alkyl. When R¹ is R⁴, non-limiting examples of R⁴ groups caninclude, for example, any of the R⁴ groups described below. Likewise,when R¹ is -alkylene-R⁴, -alkylene-R⁵, or -alkylene-R⁶, non-limitingexamples of the R⁴, R⁵, or R⁶ portion thereof can include, for example,any of the R⁴, R⁵, or R⁶ groups described below. In addition,non-limiting examples of the “alkylene” portion thereof can include, forexample, —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —CH₂CH₂CH₂CH₂—, etc. When R¹ is haloalkyl, non-limitingexamples of suitable haloalkyl groups include —CF₃, —CH₂CF₃, —CH₂F,—CF₂H, etc. When R¹ is alkenyl, non-limiting examples of suitablealkenyl groups include —CH₂CH═CH₂, —CH₂CH₂CH═CH₂, —CH₂CH═CH(CH₃),—CH₂CH═C(CH₃)₂, etc. When R¹ is alkynyl, non-limiting examples ofsuitable alkynyl groups include —CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡CH,—CH₂CH₂C≡C—CH₃, etc. When R¹ is -alkylene-O-alkyl, the alkyl andalkylene portions thereof can include, for example, any of the alkyl andalkylene groups described above, in any combination.

R² is selected from the group consisting of R⁷, alkyl, haloalkyl,-alkylene-R⁵, R⁴, R⁵, R⁶, and -alkylene-O—R⁸. When R² is R⁴, R⁵, R⁶, orR⁷, non-limiting examples of suitable R⁴, R⁵, R⁶, or R⁷ groups includethose described below. When R² is alkyl, suitable alkyl groups includemethyl, ethyl, n-propyl, 1-propyl, n-butyl, sec-butyl, t-butyl, 1-butyl,n-pentyl, neo-pentyl, iso-pentyl, etc. When R² is -alkylene-R⁵,non-limiting examples of -alkylene-R⁵ include those described above forR¹. Likewise, when R² is haloalkyl, non-limiting examples of suitablehaloalkyl groups include those described above for R¹. When R² is-alkylene-O—R⁸, non-limiting examples of the alkylene portion thereofinclude those alkylene groups described above, and non-limiting examplesof the R⁸ portion thereof includes those described below.

R³ is selected from the group consisting of alkyl, haloalkyl,-alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷. When R³ is R⁴, R⁵, R⁶, or R⁷,non-limiting examples of suitable R⁴, R⁵, R⁶, or R⁷ groups include thosedescribed below. When R³ is -alkylene-R⁵, non-limiting examples of-alkylene-R⁵ include those described above for R¹.

R² and R³ together with the carbon atom to which they are both attachedform a cycloalkyl or heterocycloalkyl ring, wherein said cycloalkyl orheterocycloalkyl ring is unsubstituted or substituted with one or moreX⁵ groups. Non-limiting examples of these cycloalkyl or heterocycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, pyrrolyl, morpholinyl, piperidinyl,piperazinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiofuranyl, tetrahydrothiopyranyl, etc.

R⁴ is unsubstituted cycloalkyl or cycloalkyl substituted with one ormore X¹ groups. Non-limiting examples of suitable cycloalkyl groupsinclude those described above.

R⁵ is unsubstituted aryl and aryl substituted with one or more X²groups. Non-limiting examples of suitable aryl groups include phenyl,naphthyl, biphenyl, etc.

R⁶ is selected from the group consisting of unsubstituted heteroaryl andheteroaryl substituted with one or more X³ groups. Non-limiting examplesof suitable heteroaryl groups include, for example, pyridyl, pyrazinyl,furanyl, thienyl, pyrimidinyl, pyridone (including N-substitutedpyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl, etc.

R⁷ is unsubstituted heterocycloalkyl and heterocycloalkyl substitutedwith one or more X⁴ groups. Non-limiting examples of suitableheterocycloalkyl groups include piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl.

R⁸ is selected from the group consisting of H, alkyl, R⁴, R⁵, R⁶, R⁷,—C(O)-alkyl, —C(O)—R⁵. When R⁸ is alkyl, non-limiting examples ofsuitable alkyl groups can include those described above for R². When R⁸is R⁴, R⁵, R⁶, or R⁷, non-limiting examples of suitable R⁴, R⁵, R⁶, orR⁷ groups include those described above. When R⁸ is —C(O)-alkyl,non-limiting examples of the alkyl portion thereof include the alkylgroups described for R². When R⁸ is —C(O)—R⁵, non-limiting examples ofR⁵ include those described above.

Each R⁹ is independently selected from the group consisting of H, alkyl,R⁴, R⁵, R⁶, and R⁷. Non-limiting examples of suitable alkyl groupsinclude those described above for R². Non-limiting examples of R⁴, R⁵,R⁶, or R⁷ include any of the groups described above for R⁴, R⁵, R⁶, andR⁷.

R¹⁰ is selected from the group consisting of R⁹, —C(O)-alkyl, and—C(O)—R⁵. When R¹⁰ is R⁹, non-limiting examples of suitable R⁹ groupsinclude those described above. When R¹⁰ is —C(O)-alkyl, non-limitingexamples of the alkyl portion thereof include the alkyl groups describedfor R². When R¹⁰ is —C(O)—R⁵, non-limiting examples of R⁵ include thosedescribed above.

Y is —O— or —N(R¹⁰)—. When Y is —N(R¹⁰)—, non-limiting examples of theR¹⁰ portion thereof include those described above.

Each X¹ and X² is independently selected from the group consisting ofhalogen, alkyl, —O-alkyl, —OH, haloalkyl, aryl, and alkyne. When X¹ orX² are halogen, suitable examples of halogen include F, Cl, Br, and I.When X¹ or X² are alkyl, non-limiting examples of suitable alkyl groupsinclude those describe above for R². When X¹ or X² are —O-alkyl,non-limiting examples of the alkyl portion thereof include thosedescribed above for R². When X¹ or X² are haloalkyl, non-limitingexamples of suitable haloalkyl groups include those described above forR¹. When X¹ or X² are aryl, non-limiting examples of suitable arylgroups include those described above for R⁵. When X¹ or X² are alkyne,non-limiting examples of suitable alkynes include ethynyl, 2-propynyl,1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, etc.

Each X³ is independently selected from the group consisting of halogen,alkyl, and N-oxide. When X³ is halogen, suitable examples of halogeninclude F, Cl, Br, and I. When X³ is alkyl, non-limiting examples ofsuitable alkyl groups include those describe above for R².

Each X⁴ is independently selected form the group consisting of alkyl,R⁵, —C(O)-alkyl, —C(O)—R⁵, —C(O)—O-alkyl, -alkylene-R⁵, R⁴, and—S(O₂)-alkyl. When X⁴ is alkyl, non-limiting examples of suitable alkylgroups include those described above for R². When X⁴ is R⁴ or R⁵,non-limiting examples of suitable R⁴ or R⁵ groups include thosedescribed above. When X⁴ is —S(O₂)-alkyl, —C(O)-alkyl, or —C(O)—O-alkyl,non-limiting examples of the alkyl portion thereof include thosedescribed above for R². When X⁴ is -alkylene-R⁵, non-limiting examplesof the alkylene portion thereof includes those described above for R¹,and the R⁵ portion thereof includes R⁵ groups described above.

Each X⁵ is independently selected from the group consisting of alkyl, afused aryl ring, —C(O)-alkyl, a fused heteroaryl ring, —C(O)—O-alkyl,—C(O)—R⁵, —S(O₂)-alkyl, —C(O)—N(R⁹)₂, R⁵, R⁶, —C(O)—R⁴, —C(O)—O—R⁴,—S(O₂)—R⁴, —S(O₂)-alkylene-R⁴, —S(O₂)-alkylene-R⁵, —N(R⁹)—C(O)—O-alkyl,—N(R⁹)—C(O)—O—R⁴, —N(R⁹)—C(O)—N(R⁹)₂ and —N(R⁹)₂; wherein said fusedaryl ring of X⁵ is unsubstituted or independently substituted with oneor more substitutent selected from -alkylene-R⁷ or X², and said fusedheteroaryl ring of X⁵ is unsubstituted or substituted with one or moreX³ groups. When X⁵ is alkyl, non-limiting examples of suitable alkylgroups include those described above for R². When X⁵ is —C(O)-alkyl,—C(O)—O-alkyl, —C(O)—R⁵, —S(O₂)-alkyl, —C(O)—N(R⁹)₂, —C(O)—R⁴,—C(O)—O—R⁴, —S(O₂)—R⁴, —S(O₂)-alkylene-R⁴, —S(O₂)-alkylene-R⁵,—N(R⁹)—C(O)—O-alkyl, —N(R⁹)—C(O)—O—R⁴, —N(R⁹)—C(O)—N(R⁹)₂ and —N(R⁹)₂,non-limiting examples of the alkyl, alkylene, R⁴, R⁵, and R⁹ portionsthereof include those described above.

When X⁵ is a fused heteroaryl ring or fused aryl ring, two adjacent ringatoms of the fused heteroaryl ring or fused aryl ring are part of thecycloalkyl or heterocycloalkyl ring to which they are fused. Examples ofan aryl ring fused to a cycloalkyl ring include a phenyl ring fused to acyclopentyl ring (i.e., indanyl).

In one embodiment, the compounds of formula (I) have the formula (II):

wherein

-   R¹ is alkyl, -alkylene-cycloalkyl, haloalkyl or -alkylene-O-alkyl;-   R² and R³ together with the carbon atom to which they are both    attached, combine to form a monocyclic cycloalkyl, bicyclic    cycloalkyl or monocyclic heterocycloalkyl, wherein a monocyclic    cycloalkyl, bicyclic cycloalkyl or monocyclic heterocycloalkyl group    is unsubstituted or optionally and independently substituted with    one or more X⁵ groups, and wherein a monocyclic cycloalkyl group may    be fused to a benzene ring, an aromatic heterocycle or a    non-aromatic heterocycle, and wherein the monocyclic cycloalkyl ring    can form a spirocyclic compound with a second cycloalkyl ring or    with a heterocycloalkyl ring, wherein the second cycloalkyl ring or    the heterocycloalkyl ring is unsubstituted or independently    substituted with one or more X⁵ groups;-   each occurrence of X⁵ is independently alkyl, —O-alkyl,    -alkylene-aryl, halo, —O—Si(R¹¹)₃, haloalkyl, —CN, —C(O)—R⁴,    —C(O)—O—R⁴, —NHC(O)—O—R⁴, —S(O₂)—R⁴, or phenyl;-   R⁴ is alkyl or cycloalkyl, wherein the cycloalkyl group can be    optionally and independently substituted with one or more X¹ groups,    and wherein the alkyl group can be optionally substituted with a    cycloalkyl group;-   each R¹¹ is independently alkyl or phenyl; and-   each occurrence of X¹ is independently halogen, alkyl, —O-alkyl,    —OH, haloalkyl, aryl or alkynyl.

The following embodiments refer to the compounds of formula (II):

In one embodiment, R¹ is alkyl.

In another embodiment, R¹ is -alkylene-cycloalkyl.

In another embodiment, R¹ is haloalkyl.

In still another embodiment, R¹ is -alkylene-O-alkyl.

In yet another embodiment, R¹ is —(CH₂)₃CF₃.

In another embodiment, R¹ is n-butyl, n-pentyl, n-hexyl, isopentyl,isohexyl or neoheptyl.

In a further embodiment, R¹ is —(CH₂)₂-cyclopropyl, —(CH₂)₃-cyclopropyl,—(CH₂)₄-cyclopropyl, —(CH₂)₂-cyclobutyl, —(CH₂)₂-cyclopentyl,—CH₂-cyclohexyl, —(CH₂)₂-cyclohexyl or

In another embodiment, R¹ is —(CH₂)₃—O—(CH₂)₂CH₃.

In one embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a monocyclic cycloalkyl group.

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a bicyclic cycloalkyl group.

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a monocyclic hetercycloalkyl group.

In still another embodiment, R², R³ and the carbon atom to which theyare both attached, combined to form a bicyclic hetercycloalkyl group.

In yet another embodiment, R², R³ and the carbon atom to which they areboth attached, combined to form a cyclopentyl or cyclohexyl group.

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a decahydronaphtyl,1,2,3,4-tetrahydronaphthyl, bicyclo[2.2.2]octyl or spiro[2.5]octylgroup.

In a further embodiment, R², R³ and the carbon atom to which they areboth attached, combined to form a piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl or tetrahydrothiopyranyl-1,1,-dioxide group

In another embodiment, R², R³ and the carbon atom to which they are bothattached, combined to form a 8-aza-bicyclo[3.2.1]octyl,1,4-dioxa-spiro[4.5]decanyl, 4,5,6,7-tetrahydro-benzo[b]thiophenyl,5,6,7,8-tetrahydroquinolinyl or 1,3-diaza-spiro[4.5]decanyl-2,4,-dionegroup.

In one embodiment, R¹ is alkyl, and R², R³ and the carbon atom to whichthey are both attached, combined to form a monocyclic cycloalkyl group.

In another embodiment, R¹ is alkyl, and R², R³ and the carbon atom towhich they are both attached, combined to form a bicyclic cycloalkylgroup.

In another embodiment, R¹ is alkyl, and R², R³ and the carbon atom towhich they are both attached, combined to form a monocyclicheterocycloalkyl group.

In still another embodiment, R¹ is alkyl, and R², R³ and the carbon atomto which they are both attached, combined to form a bicyclicheterocycloalkyl group.

In one embodiment, R¹ is haloalkyl, and R², R³ and the carbon atom towhich they are both attached, combined to form a monocyclic cycloalkylgroup.

In another embodiment, R¹ is haloalkyl, and R², R³ and the carbon atomto which they are both attached, combined to form a bicyclic cycloalkylgroup.

In another embodiment, R¹ is haloalkyl, and R², R³ and the carbon atomto which they are both attached, combined to form a monocyclicheterocycloalkyl group.

In still another embodiment, R¹ is haloalkyl, and R², R³ and the carbonatom to which they are both attached, combined to form a bicyclicheterocycloalkyl group.

In one embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ and the carbonatom to which they are both attached, combined to form a monocycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form a bicycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form amonocyclic heterocycloalkyl group.

In still another embodiment, R¹ is -alkylene-cycloalkyl, and R², R³ andthe carbon atom to which they are both attached, combined to form abicyclic heterocycloalkyl group.

In one embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and the carbonatom to which they are both attached, combined to form a monocycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form a bicycliccycloalkyl group.

In another embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form amonocyclic heterocycloalkyl group.

In still another embodiment, R¹ is -alkylene-O-alkyl, and R², R³ and thecarbon atom to which they are both attached, combined to form a bicyclicheterocycloalkyl group.

Non-limiting Illustrative examples of the compounds of formula (I),include compounds 1-285, and pharmaceutically acceptable salts,solvates, esters, and tautomers thereof, as depicted in the Examplessection below.

The present invention encompasses all metabolites of the compounds offormula (I). Such metabolites may be formed in vitro or alternatively,may be formed in vivo when a compound of formula (I) is administered toa patient.

The compounds of Formula (I) can be purified to a degree suitable foruse as a pharmaceutically active substance. That is, the compounds ofFormula (I) can have a purity of 95 wt % or more (excluding adjuvantssuch as pharmaceutically acceptable carriers, solvents, etc., which areused in formulating the compound of Formula (I) into a conventionalform, such as a pill, capsule, IV solution, etc. suitable foradministration into a patient). The purity can be 97 wt % or more, or,99 wt % or more. A purified compound of Formula (I) includes a singleisomer having a purity, as discussed above, of 95 wt % or more, 97 wt %or more, or 99 wt % or more, as discussed above.

Alternatively, the purified compound of Formula (I) can include amixture of isomers, each having a structure according to Formula (I),where the amount of impurity (i.e., compounds or other contaminants,exclusive of adjuvants as discussed above) is 5 wt % or less, 3 wt % orless, or 1 wt % or less. For example, the purified compound of Formula(I) can be an isomeric mixture of compounds of Structure (I), where theratio of the amounts of the two isomers is approximately 1:1, and thecombined amount of the two isomers is 95 wt % or more, 97 wt % or more,or 99 wt % or more.

Compounds of Formula (I), and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention. Such tautomeric forms are consideredequivalent.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Ac” means acetyl.

“Boc” means t-butyloxycarbonyl (—C(O)—O—C(CH₃)₃.

“Bu” means butyl.

“DCM” means dichloromethane (CH₂Cl₂).

“DMF” means dimethylformamide.

“CDI” means 1,1′-carbonyl diimdazole

“Et” means ethyl.

“EtO₂” or “ether” means diethyl ether.

“EtOAc” means ethylacetate.

“EtOH” means ethanol.

“HOAc” means acetic acid.

“LCMS” means liquid chromatography mass spectroscopy.

“m-CPBA” means m-chloroperoxybenzoic acid.

“Me” means methyl.

“MeOH” means methanol.

“MS” means mass spectroscopy.

“NCS” means N-chlorosuccimimide.

“NEt₃” or “Et₃N” mean triethylamine.

“satd.” means saturated.

“TFA” means trifluoroacetic acid.

“THF” means tetrahydrofuran.

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a non-human mammal,including, but not limited to, a monkey, dog, baboon, rhesus, mouse,rat, horse, cat or rabbit. In another embodiment, a patient is acompanion animal, including but not limited to a dog, cat, rabbit, horseor ferret. In one embodiment, a patient is a dog. In another embodiment,a patient is a cat.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.The alkyl groups can contain about 1 to about 12 carbon atoms in thechain, and in another embodiment, the alkyl groups can contain about 1to about 6 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl, are attached to alinear alkyl chain. “Lower alkyl” means a group having about 1 to about6 carbon atoms in the chain which may be straight or branched. The term“substituted alkyl” means that the alkyl group may be substituted by oneor more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino,—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl and t-butyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene (i.e., —CH₂—), ethylene (i.e., —CH₂CH₂— or—CH(CH₃)—), propylene (i.e., —CH₂CH₂CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)CH₂—, or—CH(CH₂CH₃)—), butylene (i.e., —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH(CH₃)—,—CH₂CH(CH₃)CH₂—, —CH(CH₂CH₂CH₃)—, etc.). “Lower alkylene” means a grouphaving about 1 to about 6 carbon atoms in the chain which may bestraight or branched.

“Alkenyl” means a hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Alkenyl groupscan have about 2 to about 12 carbon atoms in the chain; and in anotherembodiment, about 2 to about 6 carbon atoms in the chain. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, areattached to a linear alkenyl chain. “Lower alkenyl” means about 2 toabout 6 carbon atoms in the chain which may be straight or branched. Theterm “substituted alkenyl” means that the alkenyl group may besubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy, and—S(alkyl). Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl (i.e., allyl), n-butenyl, 3-methylbut-2-enyl,n-pentenyl, octenyl and decenyl.

“Alkynyl” means a hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Alkynyl groupscan have about 2 to about 12 carbon atoms in the chain, and in anotherembodiment, about 2 to about 4 carbon atoms in the chain. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, areattached to a linear alkynyl chain. “Lower alkynyl” means about 2 toabout 6 carbon atoms in the chain which may be straight or branched.Non-limiting examples of suitable alkynyl groups include ethynyl,propynyl, 2-butynyl and 3-methylbutynyl. The term “substituted alkynyl”means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, an in another embodiment,about 6 to about 10 carbon atoms. The aryl group can be optionallysubstituted with one or more “ring system substituents” which may be thesame or different, and are as defined herein. Non-limiting examples ofsuitable aryl groups include phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, and in another embodiment,about 5 to about 10 ring atoms, in which one or more of the ring atomsis an element other than carbon, for example nitrogen, oxygen or sulfur,alone or in combination. Heteroaryls can contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl, indazolyl, and the like, inwhich there is at least one aromatic ring.

“Alkylene-aryl” (or aryl-alkylene-) means a group in which the aryl andalkylene are as previously described. The bond to the parent moiety isthrough the alkylene. The alkylene moiety can be bonded to one or morearyl moieties. Alkylene-aryls can comprise a lower alkylene group.Non-limiting examples of suitable alkylene-aryl groups include benzyl,2-phenethyl, 2,2-diphenylethylene and naphthalenylmethyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Alkylaryls can comprise a lower alkyl group.Non-limiting examples of suitable alkylaryl groups include tolyl andxylyl. The bond to the parent moiety is through the aryl.

“Alkylheteroaryl” means an alkyl-heteroaryl- group in which the alkyland heteroaryl are as previously described. Alkylheteroaryls cancomprise a lower alkyl group. A non-limiting example of a suitablealkylheteroaryl group includes 2-methylpyridine. The bond to the parentmoiety is through the heteroaryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms. In one embodiment, acycloalkyl has from about 5 to about 10 ring carbon atoms. In anotherembodiment, a cycloalkyl has from about 3 to about 7 ring carbon atoms.The cycloalkyl can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined above. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalinyl, norbornyl, adamantyl and the like, as well as partiallysaturated species such as, for example, indanyl, tetrahydronaphthyl andthe like. In one embodiment, a cycloalkyl is a monocyclic cycloalkyl. Inanother embodiment, a cycloalkyl is a bicyclic cycloalkyl. In anotherembodiment, a cycloalkyl is a monocyclic cycloalkyl fused to a benzenering. In still another embodiment, a cycloalkyl is a monocycliccycloalkyl fused to an aromatic heterocycle, including, but not limitedto pyridine. In a further embodiment, a monocyclic cycloalkyl group canform a spirocycle with a second cycloalkyl group or with aheterocycloalkyl group. Illustrative examples of such spirocyclesinclude, but are not limited to:

“Cycloalkenyl” means an unsaturated, non-aromatic mono- or multicyclicring system having at least 1 carbon-carbon double bond. In oneembodiment, a cycloalkenyl has from about 5 to about 10 ring carbonatoms. In another embodiment, a cycloalkenyl has from about 3 to about 7ring carbon atoms. The cycloalkenyl can be optionally substituted withone or more “ring system substituents” which may be the same ordifferent, and are as defined above. Non-limiting examples of suitablemonocyclic cycloalkenyls include cyclopropenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and the like. Non-limiting examples ofsuitable multicyclic cycloalkyls include norbornenyl, adamantenyl andthe like.

“Cycloalkylene” means a difunctional group obtained by removal of ahydrogen atom from a cycloalkyl group that is defined above.Non-limiting examples of cycloalkylene include

“Halogen” or “halo” means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylene-aryl, alkylaryl,alkylene-heteroaryl, heteroaryl-alkenylene-, heteroaryl-alkynylene-,alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aryl-alkoxy-,acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl,aryloxycarbonyl, aryl-alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aryl-alkylthio,heteroaryl-alkylthio, cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂,—C(═NH)—NH₂, —C(═NH)—NH(alkyl), Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—,Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁ and Y₂ can be the same or differentand are independently selected from the group consisting of hydrogen,alkyl, aryl, cycloalkyl, and aryl-alkylene-. “Ring system substituent”may also mean a single moiety which simultaneously replaces twoavailable hydrogens on two adjacent carbon atoms (one H on each carbon)on a ring system. Examples of such moiety are methylenedioxy,ethylenedioxy, —C(CH₃)₂— and the like which form moieties such as, forexample:

“Heterocyclyl” or “heterocyclic” means a monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. Heterocyclyls have at least 2 ringcarbon atoms, and preferably up to about 10 ring carbon atoms. There areno adjacent oxygen and/or sulfur atoms present in the ring system.Heterocyclyls may be completely saturated, partially unsaturated, oraromatic. Aromatic heterocyclyls are termed “heteroaryl”, as definedabove. Preferred heterocyclyls contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclyl root name means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBn), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more “ring system substituents”which may be the same or different, and are as defined herein. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limitingexamples of suitable monocyclic heterocyclyl rings include saturatedheterocyclyls, for example piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, lactams, lactones, and thelike. Non-limiting examples of partially unsaturated monocyclicheterocyclyl rings include, for example, thiazolinyl, and the like.

“Heterocycloalkyl” means a monocyclic or multicyclic, saturatedheterocyclyl as defined above. In one embodiment, a heterocycloalkyl isa monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkylis a bicyclic heterocycloalkyl. In another embodiment, aheterocycloalkyl is a monocyclic heterocycloalkyl fused to a benzene. Inone embodiment, a monocyclic heterocycloalkyl has 5 or 6 ring atoms.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Alkynylalkyls can contain a loweralkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroarylalkyl” means a heteroaryl-alkyl- group in which theheteroaryl and alkyl are as previously described. Heteroaralkyls cancontain a lower alkyl group. Non-limiting examples of suitable aralkylgroups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to theparent moiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Hydroxyalkyls can contain lower alkyl. Non-limiting examples ofsuitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Acyls can contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aryl-alkyloxy” (or arylalkoxy) means an aryl-alkyl-O— group in whichthe aryl-alkyl group is as previously described. Non-limiting examplesof suitable aryl-alkyloxy groups include benzyloxy and 1- or2-naphthalenemethoxy. The bond to the parent moiety is through the etheroxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aryl-alkylthio” (or arylalkylthio) means an aryl-alkyl-S— group inwhich the aryl-alkyl group is as previously described. Non-limitingexample of a suitable aryl-alkylthio group is benzylthio. The bond tothe parent moiety is through the sulfur.

“Alkoxycarbonyl” means an alkyl-O—C(O)— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Arylalkoxycarbonyl” means an aryl-alkyl-O—C(O)— group. Non-limitingexample of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. Thebond to the parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties. An optionally substituted moietymay be unsubstituted or substituted with one or more substituents.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form” or “in isolatedand purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R¹, etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, MPS Pharm Sci Tech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the diseases or conditions noted below, and thusproducing the desired therapeutic, ameliorative, inhibitory orpreventative effect.

The compounds of Formula (I) can form salts which are also within thescope of this invention. Reference to a compound of Formula (I) hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula (I) contains both a basic moiety, such as, but not limited toa pyridine or imidazole, and an acidic moiety, such as, but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula (I) may be formed, for example, by reacting a compound ofFormula (I) with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,(C₁-C₄)alkyl, or (C₁-C₄)alkoxy or amino); (2) sulfonate esters, such asalkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acidesters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and(5) mono-, di- or triphosphate esters. The phosphate esters may befurther esterified by, for example, a (C₁-C₂₀) alcohol or reactivederivative thereof, or by a 2,3-di-(C₆-C₂₄)acyl glycerol.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, (and including those ofthe salts, solvates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs) form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers, as well as enantiomeric forms (which may exist evenin the absence of asymmetric carbons), rotameric forms, atropisomers(e.g., substituted biaryls), and diastereomeric forms. For example, if acompound of Formula (I) incorporates a double bond or a fused ring, boththe cis- and trans-forms, as well as mixtures, are embraced within thescope of the invention.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically labeled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labeled reagent for anon-isotopically labeled reagent.

Polymorphic forms of the compounds of Formula (I), and of the salts,solvates, esters and prodrugs of the compounds of Formula (I), areintended to be included in the present invention.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

The compounds of Formula (I), or pharmaceutically acceptable salts,solvates, or esters thereof according to the invention havepharmacological properties; in particular, the compounds of Formula (I)can be nicotinic acid receptor agonists.

The compounds of Formula (I) of the present invention, orpharmaceutically acceptable salts, solvates, or esters thereof areuseful in treating diseases or conditions including dyslipidemia andmetabolic syndrome.

The compounds of Formula (I), or pharmaceutically acceptable salts,solvates, or esters thereof, can be administered in any suitable form,e.g., alone, or in combination with a pharmaceutically acceptablecarrier, excipient or diluent in a pharmaceutical composition, accordingto standard pharmaceutical practice. The compounds of Formula (I), orpharmaceutically acceptable salts, solvates, or esters thereof, can beadministered orally or parenterally, including intravenous,intramuscular, interperitoneal, subcutaneous, rectal, or topical routesof administration.

Pharmaceutical compositions comprising at least one compound of Formula(I),

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof can be in a form suitable for oral administration, e.g., astablets, troches, capsules, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, syrups, or elixirs. Oralcompositions may be prepared by any conventional pharmaceutical method,and may also contain sweetening agents, flavoring agents, coloringagents, and preserving agents.

The amount of compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, ester, or tautomer thereof, administered to a patient canbe determined by a physician based on the age, weight, and response ofthe patient, as well as by the severity of the condition treated. Forexample, the amount of compound of Formula I, or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, administered tothe patient can range from about 0.1 mg/kg body weight per day to about60 mg/kg/d, preferably about 0.5 mg/kg/d to about 40 mg/kg/d.

The compounds of Formula (I), or pharmaceutically acceptable salts,solvates, or esters thereof, can also be administered in combinationwith other therapeutic agents. For example one or more compounds ofFormula (I) or pharmaceutically acceptable salts, solvates, or estersthereof, can be administered with one or more additional activeingredients selected from the group consisting of hydroxy-substitutedazetidinone compounds, substituted β-lactam compounds, HMG CoA reductaseinhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesisinhibitors, squalene epoxidase inhibitors, sterol biosynthesisinhibitors, nicotinic acid derivatives, bile acid sequestrants,inorganic cholesterol sequestrants, AcylCoA:CholesterolO-acyltransferase inhibitors, cholesteryl ester transfer proteininhibitors, fish oils containing Omega 3 fatty acids, natural watersoluble fibers, plant stanols and/or fatty acid esters of plant stanols,anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptormodulators, LXR receptor agonists, lipoprotein synthesis inhibitors,renin angiotensin inhibitors, microsomal triglyceride transport proteininhibitors, bile acid reabsorption inhibitors, PPAR δ agonists,triglyceride synthesis inhibitors, squalene epoxidase inhibitors, lowdensity lipoprotein receptor inducers or activators, plateletaggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partialagonists, niacin or niacin receptor agonists, 5HT transporterinhibitors, NE transporter inhibitors, CB₁ antagonists/inverse agonists,ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1R antagonists,MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptinagonists/modulators, leptin derivatives, opioid antagonists, orexinreceptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTFderivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists,monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1agonists, phentermine, topiramate, phytopharm compound 57, ghrelinantibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroidhormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11βHSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acidtransporter inhibitors, dicarboxylate transporter inhibitors, glucosetransporter inhibitors, phosphate transporter inhibitors, anti-diabeticagents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptorantagonists, apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamineagonists, melanocyte-stimulating hormone receptor analogs, melaninconcentrating hormone antagonists, leptons, galanin receptorantagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone, analogs of dehydroepiandrosterone,urocortin binding protein antagonists, glucagons-like peptide-1 receptoragonists, human agouti-related proteins (AGRP), neuromedin U receptoragonists, noradrenergic anorectic agents, appetite suppressants, hormonesensitive lipase antagonists, MSH-receptor analogs, α-glucosidaseinhibitors, apo A1 milano reverse cholesterol transport inhibitors,fatty acid binding protein inhibitors (FABP), and fatty acid transporterprotein inhibitors (FATP).

Non-limiting examples of hydroxy-substituted azetidinone compounds andsubstituted β-lactam compounds useful in combination with the nicotinicacid receptor agonists of the present invention are those disclosed inU.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787,5,756,470, U.S. Patent Application Nos. 2002/0137690 and 2002/0137689and PCT Patent Application No. WO 2002/066464, each of which isincorporated herein by reference in their entirety. A preferredazetidinone compound is ezetimibe (for example, ZETIA® which isavailable from Schering-Plough Corporation).

Non-limiting examples of HMG CoA reductase inhibitor compounds useful incombination with the nicotinic acid receptor agonists of the presentinvention are lovastatin (for example MEVACOR® which is available fromMerck & Co.), simvastatin (for example ZOCOR® which is available fromMerck & Co.), pravastatin (for example PRAVACHOL® which is availablefrom Bristol Meyers Squibb), atorvastatin, fluvastatin, cerivastatin,CI-981, rivastatin (sodium7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate),rosuvastatin calcium (CRESTOR® from AstraZeneca Pharmaceuticals),pitavastatin (such as NK-104 of Negma Kowa of Japan).

A non-limiting example of a HMG CoA synthetase inhibitor useful incombination with the nicotinic acid receptor agonists of the presentinvention is, for example, L-659,699((E,E)-1′-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid).

A non-limiting example of a squalene synthesis inhibitor useful incombination with the nicotinic acid receptor agonists of the presentinvention is, for example, squalestatin 1.

A non-limiting example of a squalene epoxidase inhibitor useful incombination with the nicotinic acid receptor agonists of the presentinvention is, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride).

A non-limiting example of a sterol biosynthesis inhibitor useful incombination with the nicotinic acid receptor agonists of the presentinvention is, for example, DMP-565.

Non-limiting examples of nicotinic acid derivatives (e.g., compoundscomprising a pyridine-3-carboxylate structure or apyrazine-2-carboxylate structure, including acid forms, salts, esters,zwitterions and tautomers) useful in combination with the nicotinic acidreceptor agonists of the present invention are niceritrol, nicofuranoseand acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide).

Non-limiting examples of bile acid sequestrants useful in combinationwith the nicotinic acid receptor agonists of the present invention arecholestyramine (a styrene-divinylbenzene copolymer containing quaternaryammonium cationic groups capable of binding bile acids, such asQUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available fromBristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof.

Non-limiting examples of inorganic cholesterol sequestrants useful incombination with the nicotinic acid receptor agonists of the presentinvention are bismuth salicylate plus montmorillonite clay, aluminumhydroxide and calcium carbonate antacids.

Non-limiting examples of AcylCoA:Cholesterol O-acyltransferase (“ACAT”)inhibitors useful in combination with the nicotinic acid receptoragonists of the present invention are avasimibe([[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamic acid,2,6-bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004,lecimibide (DuP-128) and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea),and the compounds described in P. Chang et al., “Current, New and FutureTreatments in Dyslipidaemia and Atherosclerosis”, Drugs 2000 July;60(1); 55-93, which is incorporated by reference herein.

Non-limiting examples of cholesteryl ester transfer protein (“CETP”)inhibitors useful in combination with the nicotinic acid receptoragonists of the present invention are those disclosed in PCT PatentApplication No. WO 00/38721, U.S. Pat. Nos. 6,147,090, 6,958,346,6,924,313 6,906,082, 6,861,561, 6,803,388, 6,794,396, 6,787,570,6,753,346, 6,723,752, 6,723,753, 6,710,089, 6,699,898, 6,696,472,6,696,435, 6,683,113, 5,519,001, 5,512,548, 6,410,022, 6,426,365,6,448,295, 6,387,929, 6,683,099, 6,677,382, 6,677,380, 6,677,379,6,677,375, 6,677,353, 6,677,341, 6,605,624, 6,586,433, 6,451,830,6,451,823, 6,462,092, 6,458,849, 6,458,803, 6,455,519, 6,583,183,6,562,976, 6,555,113, 6,544,974, 6,521,607, 6,489,366, 6,482,862,6,479,552, 6,476,075, 6,476,057, and 6,897,317, each of which areincorporated herein by reference; compounds described in Yan Xia et al.,“Substituted 1,3,5-Triazines As Cholesteral Ester Transfer ProteinInhibitors”, Bioorganic & Medicinal Chemistry Letters, vol. 6, No. 7,1996, pp. 919-922, herein incorporated by reference; natural productsdescribed in S. Coval et al., “Wiedendiol-A and -B, Cholesteryl EsterTransfer Protein Inhibitors From The Marine Sponge XestospongaWiedenmayeri”, Bioorganic & Medicinal Chemistry Letter, vol. 5, No. 6,pp. 605-610, 1995, herein incorporated by reference; the compoundsdescribed in Barrett et al. J. Am. Chem. Soc., 188, 7863-63 (1996),herein incorporated by reference; the compounds described in Kuo et al.J. Am. Chem. Soc., 117, 10629-34 (1995), herein incorporated byreference; the compounds described in Pietzonka et al. Bioorg. Med.Chem. Lett., 6, 1951-54 (1996), herein incorporated by reference; thecompounds described in Lee et al. J. Antibiotics, 49, 693-96 (1996),herein incorporated by reference; the compounds described by Busch etal. Lipids, 25, 216-220, (1990), herein incorporated by reference; thecompounds described in Morton and Zilversmit J. Lipid Res., 35, 836-47(1982), herein incorporated by reference; the compounds described inConnolly et al. Biochem. Biophys. Res. Comm., 223, 42-47 (1996), hereinincorporated by reference; the compounds described in Bisgaier et al.Lipids, 29, 811-8 (1994), herein incorporated by reference; thecompounds described in EP 818448, herein incorporated by reference; thecompounds described in JP 10287662, herein incorporated by reference;the compounds described in PCT applications WO 98/35937, WO 9914174, WO9839299, and WO 9914215, each of which is herein incorporated byreference; the compounds of EP applications EP 796846, EP 801060,818448, and 818197, each of which is herein incorporated by reference;probucol or derivatives thereof, such as AGI-1067 and other derivativesdisclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250, herein incorporatedby reference; low-density lipoprotein (LDL) receptor activators such asHOE-402, an imidazolidinyl-pyrimidine derivative that directlystimulates LDL receptor activity, described in M. Huettinger et al.,“Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDLReceptor Pathway”, Arterioscler. Thromb. 1993; 13:1005-12, hereinincorporated by reference;4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines, e.g.,torcetrapib, described in WO 00/017164, WO 00/017166, WO 00/140190, WO00/213797, and WO 2005/033082 (each of which is herein incorporated byreference). Torcetrapib can be combined with HMG-CoA reductaseinhibitors such as atorvastatin (WO 00/213797, WO 2004/056358, WO2004/056359, and WO2005/011634).

A non-limiting example of a fish oil containing Omega 3 fatty acidsuseful in combination with the nicotinic acid receptor agonists of thepresent invention is 3-PUFA.

Non-limiting examples of natural water soluble fibers useful incombination with the nicotinic acid receptor agonists of the presentinvention are psyllium, guar, oat and pectin.

A non-limiting example of a plant stanol and/or fatty acid ester ofplant stanols useful in combination with the nicotinic acid receptoragonists of the present invention is the sitostanol ester used inBENECOL® margarine.

A non-limiting example of an anti-oxidant useful in combination with thenicotinic acid receptor agonists of the present invention includesprobucol.

Non-limiting examples of PPAR α agonists useful in combination with thenicotinic acid receptor agonists of the present invention includebeclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate,fenofibrate, and gemfibrozil.

Non-limiting examples of lipoprotein synthesis inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include niacin or nicotinic acid.

Non-limiting examples of 5HT (serotonin) transport inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertraline, and imipramine.

Non-limiting examples of NE (norepinephrine) transport inhibitors usefulin combination with the nicotinic acid receptor agonists of the presentinvention include GW 320659, despiramine, talsupram, and nomifensine.

Non-limiting examples of CB₁ antagonists/inverse agonists useful incombination with the nicotinic acid receptor agonists of the presentinvention include rimonabant, SR-147778 (Sanofi Synthelabo), and thecompounds described in U.S. Pat. No. 5,532,237, U.S. Pat. No. 4,973,587,U.S. Pat. No. 5,013,837, U.S. Pat. No. 5,081,122, U.S. Pat. No.5,112,820, U.S. Pat. No. 5,292,736, U.S. Pat. No. 5,624,941, U.S. Pat.No. 6,028,084, WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO01/09120, WO 98/31227, WO 98/41519, WO 98/37061, WO 00/10967, WO00/10968, WO 97/29079, WO 99/02499, WO 01/58869, WO 02/076949, andEP-658546 (each of the preceding references is herein incorporated byreference).

Non-limiting examples of ghrelin antagonists useful in combination withthe nicotinic acid receptor agonists of the present invention includethose described in WO 01/87335 and WO 02/08250 (each of the precedingreferences is herein incorporated by reference). Ghrelin antagonists arealso known as GHS (growth hormone secretagogue receptor) antagonists.The pharmaceutical combinations and methods of the present inventiontherefore comprehend the use GHS antagonists in place of ghrelinantagonists (in combination with the nicotinic acid receptor agonists ofthe present invention).

Non-limiting examples of H₃ antagonists/inverse agonists useful incombination with the nicotinic acid receptor agonists of the presentinvention include thioperamide, 3-(1H-imidazol-4-yl)propylN-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, andGT2394 (Gliatech), those described in WO 02/15905 (herein incorporatedby reference); O-[3-(1H-imidazol-4-yl)propanol]carbamates described inKiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000) (hereinincorporated by reference), piperidine-containing histamine H₃-receptorantagonists described in Lazewska, D. et al., Pharmazie, 56:927-32(2001) (herein incorporated by reference), benzophenone derivatives andrelated compounds described in Sasse, A. et al., Arch. Pharm. (Weinheim)334:45-52 (2001)(herein incorporated by reference), substitutedN-phenylcarbamates described in Reidemeister, S. et al., Pharmazie,55:83-6 (2000)(herein incorporated by reference), and proxifanderivatives described in Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)(each of the preceding references is herein incorporated byreference).

Non-limiting examples of MCH1R (melanin-concentrating hormone 1receptor) antagonists and MCH2R (melanin-concentrating hormone 2receptor) agonists/antagonists useful in combination with the nicotinicacid receptor agonists of the present invention include those describedin WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO 02/51809, andJP 13226269 (each of the preceding references is herein incorporated byreference), and T-226296 (Takeda).

Non-limiting examples of NPY1 antagonists useful in combination with thenicotinic acid receptor agonists of the present invention include thosedescribed in U.S. Pat. No. 6,001,836, WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 (eachof the preceding references is herein incorporated by reference); andBIBP3226, J=115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A.

Non-limiting examples of NPY5 antagonists useful in combination with thenicotinic acid receptor agonists of the present invention include thosedescribed in U.S. Pat. No. 6,140,354, U.S. Pat. No. 6,191,160, U.S. Pat.No. 6,258,837, U.S. Pat. No. 6,313,298, U.S. Pat. No. 6,337,332, U.S.Pat. No. 6,329,395, U.S. Pat. No. 6,340,683, U.S. Pat. No. 6,326,375,U.S. Pat. No. 6,335,345, EP-01010691, EP-01044970, WO 97/19682, WO97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/85714, WO01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO02/22592, WO 0248152, WO 02/49648, WO 01/14376, WO 04/110375, WO05/000217 and Norman et al., J. Med. Chem. 43:4288-4312 (2000) (each ofthe preceding references is herein incorporated by reference); and152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X; FR226928, FR240662, FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170,SR-120562A, SR-120819A and JCF-104.

Non-limiting examples of NPY2 agonists useful in combination with thenicotinic acid receptor agonists of the present invention includePYY3-36 as described in Batterham, et al., Nature. 418:650-654 (2003),NPY3-36, and other Y2 agonists such as N acetyl [Leu(28,31)] NPY 24-36(White-Smith and Potter, Neuropeptides 33:526-33 (1999)), TASP-V (Maliset al., Br. J. Pharmacol. 126:989-96 (1999)),cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY (Cabrele and Beck-SickingerJ-Pept-Sci. 6:97-122 (2000)) (each of the preceding references is hereinincorporated by reference).

Non-limiting examples of NPY4 agonists useful in combination with thenicotinic acid receptor agonists of the present invention includepancreatic peptide (PP) as described in Batterham et al., J. Clin.Endocrinol. Metab. 88:3989-3992 (2003), and other Y4 agonists such as1229U91 (Raposinho et al., Neuroendocrinology. 71:2-7(2000) (bothreferences are herein incorporated by reference).

Non-limiting examples of mGluR5 (Metabotropic glutamate subtype 5receptor) antagonists useful in combination with the nicotinic acidreceptor agonists of the present invention include2-methyl-6-(phenylethynyl)-pyridine (MPEP) and(3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) (MTEP) and thosecompounds described in Anderson J. et al., J, Eur J Pharmacol. Jul. 18,2003; 473(1):35-40; Cosford N. et al., Bioorg Med Chem Lett. Feb. 10,2003; 13(3):351-4; and Anderson J. et al., J Pharmacol Exp Ther.December 2002:303(3):1044-51 (each of the preceding references is hereinincorporated by reference).

Non-limiting examples of leptins, leptin derivatives, and leptinagonists/modulators useful in combination with the nicotinic acidreceptor agonists of the present invention include recombinant humanleptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin(Amgen). Leptin derivatives (e.g., truncated forms of leptin) useful inthe present invention include those described in U.S. Pat. No.5,552,524, U.S. Pat. No. 5,552,523, U.S. Pat. No. 5,552,522, U.S. Pat.No. 5,521,283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO96/23517, WO 96/23518, WO 96/23519, and WO 96/23520 (each of thepreceding references is herein incorporated by reference).

Non-limiting examples of opioid antagonists useful in combination withthe nicotinic acid receptor agonists of the present invention includenalmefene (Revex™), 3-methoxynaltrexone, naloxone, and naltrexone, aswell as opioid antagonists described in WO 00/21509 (herein incorporatedby reference).

Non-limiting examples of orexin receptor antagonists useful incombination with the nicotinic acid receptor agonists of the presentinvention include SB-334867-A, as well as those described in WO01/96302, WO 01/68609, WO 02/51232, and WO 02/51838 (each of thepreceding references is herein incorporated by reference).

Non-limiting examples of CNTF (specific ciliary neurotrophic factors)useful in combination with the nicotinic acid receptor agonists of thepresent invention include GI-181771 (Glaxo-SmithKline); SR146131 (SanofiSynthelabo); butabindide; PD170,292, PD 149164 (Pfizer).

Non-limiting examples of CNTF derivatives and CNTF agonists/modulatorsuseful in combination with the nicotinic acid receptor agonists of thepresent invention include axokine (Regeneron) and those described in WO94/09134, WO 98/22128, and WO 99/43813 (each of which is hereinincorporated by reference).

Non-limiting examples of 5HT2c agonists useful in combination with thenicotinic acid receptor agonists of the present invention includeBVT933, DPCA37215, WAY161503, and R-1065, as well as those described inU.S. Pat. No. 3,914,250, WO 02/36596, WO 02/48124, WO 02/10169, WO01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457 (eachof which is herein incorporated by reference).

Non-limiting examples of Mc4r agonists useful in combination with thenicotinic acid receptor agonists of the present invention includeCHIR86036 (Chiron); ME-10142, and ME-10145 (Melacure), as well as thosedescribed in WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO02/12178 (each of which is herein incorporated by reference).

Non-limiting examples of monoamine reuptake inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include sibutramine (Meridia™/Reductil™), as well as thosedescribed in WO 01/27068, WO 01/62341, U.S. Pat. No. 4,746,680, U.S.Pat. No. 4,806,570, U.S. Pat. No. 5,436,272, and US 2002/0006964 (eachof which is herein incorporated by reference).

Non-limiting examples of serotonin reuptake inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include dexfenfluramine, fluoxetine, and those described inU.S. Pat. No. 6,365,633, WO 01/27060, and WO 01/162341 (each of which isherein incorporated by reference).

Non-limiting examples of GLP-1 agonists useful in combination with thenicotinic acid receptor agonists of the present invention includeexendin-3 and exendin-4.

A non-limiting example of an acyl-estrogen useful in combination withthe nicotinic acid receptor agonists of the present invention includesoleoyl-estrone.

Non-limiting examples of 11β HSD-1 inhibitors useful in combination withthe nicotinic acid receptor agonists of the present invention includethose described in WO 03/065983 and WO 03/104207 (both of which areherein incorporated by reference).

A non-limiting example of a lipase inhibitor useful in combination withthe nicotinic acid receptor agonists of the present invention includeorlistat.

Anti-diabetic agents useful in combination with the nicotinic acidreceptor agonists of the present invention include sulfonylureas,meglitinides, α-amylase inhibitors, α-glucoside hydrolase inhibitors,PPAR-γ agonists, PPARα/γ agonists, biguanides, PTP-1B inhibitors, DP-IVinhibitors, insulin secreatagogues, fatty acid oxidation inhibitors, A2antagonists, c-jun amino-terminal kinase inhibitors, insulin, insulinmimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists,glucokinase activators, and non-thiazolidinedione PPAR ligands.Non-limiting examples of sulfonylureas useful in combination with thenicotinic acid receptor agonists of the present invention includeacetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide,glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, and tolbutamide.

Non-limiting examples of meglitinides useful in combination with thenicotinic acid receptor agonists of the present invention includerepaglinide and nateglinide.

Non-limiting examples of α-amylase inhibitors useful in combination withthe nicotinic acid receptor agonists of the present invention includetendamistat, trestatin, and AI-3688.

Non-limiting examples of α-glucoside hydrolase inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include acarbose, adipose, camiglibose, emiglitate, miglitol,voglibose, pradimicin-Q, salbostatin, CDK-711, MDL-25,637, MDL-73,945,and MOR 14.

Non-limiting examples of PPAR-γ agonists useful in combination with thenicotinic acid receptor agonists of the present invention includebalaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone(MCC-555), pioglitazone, rosiglitazone, troglitazone, tesaglitazar,netoglitazone, GW409544, GW-501516, CLX-0921, 5-BTZD, GW-0207,LG-100641, LY-300512, LY-519818, R483 (Roche), and T131 (Tularik).

Non-limiting examples of PPARα/γ agonists useful in combination with thenicotinic acid receptor agonists of the present invention includeCLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767,and SB 219994.

Non-limiting examples of biguanides useful in combination with thenicotinic acid receptor agonists of the present invention includebuformin, metformin, and phenformin.

Non-limiting examples of PTP-1B inhibitors (protein tyrosinephosphatase-1B inhibitors) useful in combination with the nicotinic acidreceptor agonists of the present invention include A-401,674, KR 61639,OC-060062, OC-83839, OC-297962, MC52445, and MC52453.

Non-limiting examples of DP-IV inhibitors (dipeptidyl peptidase IViinhibitors) useful in combination with the nicotinic acid receptoragonists of the present invention include isoleucine thiazolidide,NVP-DPP728, P32/98, LAF 237, TSL 225, valine pyrrolidide, TMC-2A/2B/2C,CD-26 inhibitors, and SDZ 274-444.

Non-limiting examples of insulin secreatagogues useful in combinationwith the nicotinic acid receptor agonists of the present inventioninclude linogliride and A-4166.

Non-limiting examples of fatty acid oxidation inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include clomoxir and etomoxir.

Non-limiting examples of A2 antagonists useful in combination with thenicotinic acid receptor agonists of the present invention includemidaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan.

Non-limiting examples of insulin mimetics useful in combination with thenicotinic acid receptor agonists of the present invention include biota,LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine,insulin zinc suspension (lente and ultralente), Lys-Pro insulin, GLP-1(73-7) (insulintropin), and GLP-1 (7-36)-NH₂).

Non-limiting examples of glycogen phosphorylase inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include CP-368,296, CP-316,819, and BAYR3401.

Non-limiting examples of non-thiazolidinedione PPAR ligands useful incombination with the nicotinic acid receptor agonists of the presentinvention include JT-501 and farglitazar (GW-2570/GI-262579).

Anti-hypertensive agents useful in combination with the nicotinic acidreceptor agonists of the present invention include diuretics,β-adrendergic blockers, α-adrenergic blockers, aldosterone inhibitors,alpha 1 blockers, calcium channel blockers, angiotensin convertingenzyme inhibitors, neutral endopeptidase inhibitors, angiotensin 11receptor antagonists, endothelin antagonists, vasodilators, alpha 2aagonists, and α/β adrenergic blockers.

Non-limiting examples of diuretics useful in combination with thenicotinic acid receptor agonists of the present invention includechlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide,indapamide, hydrochlorothiazide, bumetanide, ethacrynic acid,furosemide, torsemide, amiloride, triamterene, spironolactone, andepirenone.

Non-limiting examples of β-adrendergic blockers useful in combinationwith the nicotinic acid receptor agonists of the present inventioninclude acebutolol, atenolol, betaxolol, bevantolol, bisoprolol,bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol,metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol,sotalol, tertatolol, tilisolol, and timolol.

Non-limiting examples of alpha 1 blockers useful in combination with thenicotinic acid receptor agonists of the present invention includeterazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin,naftopidil, indoramin, WHIP 164, and XEN010.

Non-limiting examples of calcium channel blockers useful in combinationwith the nicotinic acid receptor agonists of the present inventioninclude amlodipine, aranidipine, azelnidipine, barnidipine, benidipine,bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine,gallopamil, isradipine, lacidipine, lemildipine, lercanidipine,nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine,nitrendipine, manidipine, pranidipine, and verapamil.

Non-limiting examples of angiotensin converting enzyme inhibitors usefulin combination with the nicotinic acid receptor agonists of the presentinvention include alacepril, benazepril, ceronapril, captopril,cilazapril, delapril, enalapril, fosinopril, imidapril, losinopril,moveltopril, moexipril, quinapril, quinaprilat, ramipril, perindopril,peridropril, quanipril, spirapril, temocapril, trandolapril, andzofenopril.

Non-limiting examples of neutral endopeptidase inhibitors useful incombination with the nicotinic acid receptor agonists of the presentinvention include omapatrilat, cadoxatril, ecadotril, fosidotril,sampatrilat, AVE7688, and ER4030.

Non-limiting examples of angiotensin 11 receptor antagonists useful incombination with the nicotinic acid receptor agonists of the presentinvention include candesartan, eprosartan, irbesartan, losartan,pratosartan, tasosartan, telisartan, valsartan, EXP-3137, F16828K,RNH6270, losartan monopotassium, and losartanpotassium-hydrochlorothiazide.

Non-limiting examples of endothelin antagonists useful in combinationwith the nicotinic acid receptor agonists of the present inventioninclude tezosentan, A308165, and YM62899.

Non-limiting examples of vasodilators useful in combination with thenicotinic acid receptor agonists of the present invention includehydralazine (apresoline), clonidine (catapres), minoxidil (loniten), andnicotinyl alcohol (roniacol).

Non-limiting examples of alpha 2a agonists useful in combination withthe nicotinic acid receptor agonists of the present invention includelofexidine, tiamenidine, moxonidine, rilmenidine, and guanobenz.

Non-limiting examples of α/β adrenergic blockers useful in combinationwith the nicotinic acid receptor agonists of the present inventioninclude nipradilol, arotinolol, and amosulalol.

DP receptor antagonists useful in combination with the nicotinic acidreceptor agonists of the present invention include those described in US2004/0229844 (herein incorporated by reference).

In addition, the nicotinic acid receptor agonists of the presentinvention can also be used in combination with two or more therapeuticagents. A non-limiting example of two or more therapeutic agents usefulin combination with the nicotinic acid receptor agonists of the presentinvention is the combination of a compound of the present invention withVYTORIN® (a combination of simvastatin and ezetimibe).

EXAMPLES General Procedure for Preparation of piperazine Oxime: Example1

A solution of aldehyde (1 eq) in MeOH (ca. 1 M concentration) was addedwith NH₂OH.HCl (1.2 eq) and NaOAc (1.2 eq) and stirred at roomtemperature overnight. Then the resulting mixture was filtered, and thefiltrate was concentrated, diluted with CH₂Cl₂, washed with water, driedover Na₂SO₄ and concentrated to give crude product 1a.

The crude product 1a was dissolved in DMF (ca. 2M concentration) and NCS(1.2 eq) was added portion-wise at 0° C. The resulting mixture wasstirred at room temperature overnight and then diluted with water andextracted with ether. The ether layer was washed with brine, dried overNa₂SO₄ and concentrated to give crude oximinoyl chloride 1b.

The crude oximinoyl chloride 1 b was dissolved in ether (ca. 1 Mconcentration) and N-methylpiperazine (1.2 eq) was added slowly. Theresulting mixture was stirred at room temperature overnight andconcentrated. The residue was dissolved in CH₂Cl₂ and washed with waterand brine. The organic layer was dried over Na₂SO₄, concentrated andpurified by silica gel chromatography (CH₂Cl₂:MeOH/10:1-5:1) to affordpiperazine amidoxime 1c (geometry unassigned).

To a mixture of sulfoxide 1d (prepared as described below) (1 eq) andpiperazine amidoxime 1c (1.5 eq) in THF/CH₃CH (1:1, ca. 0.1 Mconcentration) was added NaH (2.2 eq) and the resulting mixture wasstirred at room temperature overnight. Then the reaction mixture wasquenched with sat. aqueous NH₄Cl, extracted with CH₂Cl₂, dried overNa₂SO₄, concentrated and purified by silica gel chromatography(CH₂Cl₂:MeOH=12:1) to afford product (unassigned geometry). (The silicagel column was eluted with CH₂Cl₂:MeOH:Et₃N=20:2:1 before thechromatographic separation).

Preparation of Sulfoxide

A mixture of 4,6-dihydroxy-2-mercapto-pyrimidine (20.0 g, 138.7 mmol)and methyl propionylacetate (21.8 mL, 173.4 mmol) was heated at 165° C.until the ester was completely reacted. The reaction mixture was cooleddown and poured into water (75 mL) and then filtered through a sinteredfunnel. The solid residue was washed with water (2×20 mL) and driedunder vacuum to yield5-ethyl-2-thioxo-2,3-dihydro-1h-pyrano[2,3-d]pyrimidine-4,7-dione (11.6g, 37%).

MeI (2.23 mL, 35.72 mmol) was added to a suspension of5-ethyl-2-thioxo-2,3-dihydro-1h-pyrano[2,3-d]pyrimidine-4,7-dione (4.0g, 17.86 mmol) in DMF (40 mL) at room temperature. The reaction mixturewas stirred at room temperature overnight. The reaction mixture was thenpoured into water (250 mL) and filtered through a sintered funnel. Thesolid residue was washed with water (2×50 mL) and dried under vacuum togive 5-ethyl-2-methylsulfanyl-3H-pyrano[2,3-d]pyrimidine-4,7-dione (4.1g, 96%).

m-CPBA (3.1 g, 70%, 12.6 mmol) was added to a suspension of5-ethyl-2-methylsulfanyl-3h-pyrano[2,3-d]pyrimidine-4,7-dione (2.0 g,8.4 mmol) in CH₂Cl₂ (150 mL) at room temperature. The solvent wasremoved from the suspension after 3 hours and the crude product waspurified using silica gel flash column chromatography, eluting firstwith hexane/EtOAc (v/v=1/1) then CH₂Cl₂/MeOH (v/v=2/1) to give 1d (2.0g, 94%). Electrospray MS [M+1]⁺255.1.

The following compounds were prepared following the general procedure ofExample 1, steps A-D, using the appropriate starting materials (e.g.,the appropriate aldehyde and/or heterocycloalkyl reagent):

White powder (37% yield); ¹H NMR (DMSO): δ 0.95 (t, 3H, J=7.3 Hz), 1.14(t, 3H, J=7.6 Hz), 1.54-1.44 (m, 2H), 2.25 (s, 3H), 2.45-2.38 (m, 4H),2.56-2.50 (m, 2H), 2.97-2.89 (m, 2H), 3.42-3.36 (m, 4H), 5.91 (s, 1H);Mass for C₁₈H₂₆N₅O₄ (MH)⁺: 376, Found: 376.

White powder (25% yield); ¹H NMR (DMSO): δ 1.04 (t, 3H, J=7.3 Hz), 1.11(t, 3H, J=7.3 Hz), 2.21 (s, 3H), 2.42-2.34 (m, 4H), 2.57-2.47 (m, 2H),2.95-2.85 (m, 2H), 3.41-3.32 (m, 4H), 5.87 (s, 1H); Mass for C₁₇H₂₄N₅O₄(MH)⁺: 362, Found: 362.

White powder (24% yield); ¹H NMR (DMSO): δ 0.88 (t, 3H, J=6.6 Hz), 1.11(t, 3H, J=6.7 Hz), 1.46-1.27 (m, 4H), 2.21 (s, 3H), 2.42-2.33 (m, 4H),2.55-2.46 (m, 2H), 2.95-2.86 (m, 2H), 3.40-3.30 (m, 4H), 5.88 (s, 1H);Mass for C₁₉H₂₈N₅O₄ (MH)⁺: 390, Found: 390.

White powder (30% yield); ¹H NMR (DMSO): δ 0.91 (d, 6H, J=5.9 Hz), 1.11(t, 3H, J=8.4 Hz), 1.89-1.73 (m, 1H), 2.22 (s, 3H), 2.43-2.33 (m, 4H),2.53-2.43 (m, 2H), 2.96-2.83 (m, 2H), 3.44-3.33 (m, 4H), 5.89 (s, 1H);Mass for C₁₉H₂₈N₅O₄ (MH)⁺: 390, Found: 390.

White powder (23% yield); ¹H NMR (DMSO): δ 0.96 (s, 9H), 1.11 (t, 3H,J=7.3 Hz), 2.23 (s, 3H), 2.44-2.37 (m, 4H), 2.56 (s, 2H), 2.95-2.85 (m,2H), 3.42-3.33 (m, 4H), 5.89 (s, 1H); Mass for C₂₀H₃₀N₅O₄ (MH)⁺: 404,Found: 404.

Off-white powder (38% yield); ¹H NMR (CDCl₃): δ 0.88-0.81 (m, 2H), 1.01(t, 3H, J=6.3 Hz), 1.28-1.21 (m, 2H), 1.55-1.43 (m, 2H), 1.70-1.57 (m,3H), 2.42 (s, 3H), 2.59-2.52 (m, 4H), 3.01 (t, 2H, J=8.1 Hz), 3.41-3.61(m, 4H), 5.98 (s, 1H); Mass for C₂₀H₂₇N₅O₄ (MH)⁺: 402, Found: 402.

White powder (24% yield); ¹H NMR (DMSO): δ 1.16 (t, 3H, J=7.4 Hz), 2.47(s, 3H), 2.56-2.38 (m, 6H), 2.83-2.73 (m, 2H), 2.96-2.86 (m, 2H),3.42-3.32 (m, 4H), 5.90 (s, 1H); Mass for C₁₈H₂₃F₃N₅O₄ (MH)⁺: 430,Found: 430.

White powder (26% yield); ¹H NMR (DMSO): δ 1.15 (t, 3H, J=7.6 Hz), 2.24(s, 3H), 2.41-2.35 (m, 4H), 2.88-2.74 (m, 4H), 2.98-2.90 (m, 2H),3.40-3.30 (m, 4H), 5.90 (s, 1H), 7.30-7.10 (m, 5H); Mass for C₂₃H₂₈N₅O₄(MH)⁺: 438, Found: 438.

White powder (31% yield); ¹H NMR (DMSO): δ 0.95 (t, 3H, J=7.3 Hz), 1.04(t, 3H, J=6.9 Hz), 1.14 (t, 3H, J=7.3 Hz), 1.55-1.43 (m, 2H), 2.58-2.38(m, 8H), 2.98-2.88 (m, 2H), 3.45-3.36 (m, 4H), 5.92 (s, 1H); Mass forC₁₉H₂₈N₅O₄ (MH)⁺: 390, Found: 390.

White powder (26% yield); ¹H NMR (DMSO): δ 0.98 (t, 3H, J=7.6 Hz), 1.15(t, 3H, J=7.3 Hz), 1.58-1.48 (m, 2H), 2.62-2.55 (m, 2H), 2.98-2.90 (m,2H), 3.07-2.98 (m, 4H), 3.61-3.51 (m, 4H), 5.95 (s, 1H), 7.09-6.97 (m,1H), 7.17-7.08 (m, 1H), 7.29-7.19 (m, 1H); Mass for C₂₃H₂₆F₂N₅O₄ (MH)⁺:474, Found: 474.

Off-white powder (18% yield); ¹H NMR (DMSO): δ 0.98 (t, 3H, J=7.6 Hz),1.15 (t, 3H, J=7.6 Hz), 1.57-1.49 (m, 2H), 2.62-2.55 (m, 2H), 2.97-2.91(m, 2H), 3.23-3.16 (m, 4H), 3.59-3.52 (m, 4H), 5.94 (s, 1H), 6.83 (t,1H, J=7.5 Hz), 7.02-6.96 (m, 2H), 7.28-7.23 (m, 2H); Mass for C₂₃H₂₈N₅O₄(MH)⁺: 438, Found: 438.

White powder (33% yield); ¹H NMR (CD₃OD): δ 1.04 (t, 3H, J=6.9 Hz), 1.22(t, 3H, J=7.3 Hz), 1.67-1.55 (m, 2H), 2.14 (s, 2H), 2.67 (t, 2H, J=8.5Hz), 3.08-2.98 (m, 2H), 3.57-3.43 (m, 4H), 3.70-3.59 (m, 4H), 5.96 (s,1H); Mass for C₁₉H₂₆N₅O₅ (MH)⁺: 404, Found: 404.

Brown powder (19% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=7.3 Hz), 1.11(t, 3H, J=6.6 Hz), 1.52-1.38 (m, 2H), 2.42-2.34 (m, 4H), 2.53-2.45 (m,2H), 2.97-2.86 (m, 2H), 3.39-3.33 (m, 4H), 3.52-3.47 (s, 2H), 5.90 (s,1H), 7.36-7.20 (m, 5H); Mass for C₂₄H₃₀N₅O₄ (MH)⁺: 452, Found: 452.

White powder (25% yield); ¹H NMR (DMSO): δ 1.89-0.81 (m, 19H), 2.40-2.24(m, 2H), 2.69-2.42 (m, 4H), 3.07-2.87 (m, 4H), 3.40-3.23 (m, 2H), 5.89(s, 1H), 9.18 (s, 1H); Mass for C₂₃H₃₄N₅O₄ (MH)⁺: 444, Found: 444.

Off-white powder (21% yield); ¹H NMR (DMSO): δ 0.96 (t, 3H, J=7.2 Hz),1.09 (t, 3H, J=7.6 Hz), 1.70-1.50 (m, 8H), 2.57-2.45 (m, 2H), 2.87-2.79(m, 2H), 3.62-3.48 (m, 4H), 5.28 (s, 1H); Mass for C₁₈H₂₅N₄O₄ (MH)⁺:361, Found: 361.

Brown oil (19% yield); ¹H NMR (DMSO): δ 1.80-0.90 (m, 16H), 2.69-2.61(m, 2H), 2.92-2.82 (m, 2H), 3.07-2.98 (m, 2H), 4.10-4.01 (m, 2H), 5.96(s, 1H); Mass for C₁₉H₂₇N₄O₄ (MH)⁺: 375, Found: 375.

White powder (40% yield); ¹H NMR (DMSO): δ 0.96 (t, 3H, J=7.3 Hz), 1.14(t, 3H, J=7.3 Hz), 1.56-1.45 (m, 2H), 2.57-2.50 (m, 2H), 2.98-2.90 (m,2H), 3.42-3.36 (m, 4H), 3.67-3.61 (m, 4H), 5.94 (s, 1H), 12.70-12.39 (brs, 1H); Mass for C₁₇H₂₃N₄O₅ (MH)⁺: 363, Found: 363.

White powder (29% yield); ¹H NMR (DMSO): δ 0.96 (t, 3H, J=6.9 Hz), 1.14(t, 3H, J=7.2 Hz), 1.57-1.44 (m, 2H), 1.93-1.83 (m, 2H), 2.58-2.33 (m,5H), 2.80-2.62 (m, 4H), 3.00-2.88 (m, 2H), 3.66-3.42 (m, 4H), 5.87 (s,1H); Mass for C₁₉H₂₈N₅O₄ (MH)⁺: 390, Found: 390.

White powder (34% yield); ¹H NMR (CD₃OD): δ 0.99 (t, 3H, J=7.3 Hz), 1.05(t, 3H, J=7.2 Hz), 1.53-1.41 (m, 2H), 1.68-1.55 (m, 4H), 2.43 (s, 3H),2.70-2.59 (m, 6H), 3.04-2.98 (m, 2H), 3.57-3.49 (m, 4H), 5.92 (s, 1H);Mass for C₂₀H₃₀N₅O₄ (MH)⁺: 404, Found: 404.

White powder (33% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=7.3 Hz), 1.07(t, 3H, J=7.6 Hz), 1.42-1.31 (m, 2H), 1.58-1.44 (m, 2H), 2.26 (s, 3H),2.60-2.38 (m, 6H), 2.95-2.85 (m, 2H), 3.45-3.32 (m, 4H), 5.91 (s, 1H);Mass for C₁₉H₂₈N₅O₄ (MH)⁺: 390, Found: 390.

White powder (33% yield); ¹H NMR (CD₃OD): δ 1.02-0.96 (m, 6H), 1.68-1.40(m, 8H), 2.43 (s, 3H), 2.73-2.58 (m, 6H), 3.06-2.96 (m, 2H), 3.58-3.48(m, 4H), 5.94 (s, 1H); Mass for C₂₁H₃₂N₅O₄ (MH)⁺: 418, Found: 418.

White powder (23% yield); ¹H NMR (DMSO): δ 1.01-0.85 (m, 9H), 1.43-1.30(m, 2H), 1.56-1.44 (m, 2H), 1.91-1.77 (m, 1H), 2.26 (s, 3H), 2.59-2.34(m, 6H), 2.95-2.84 (m, 2H), 3.47-3.37 (m, 4H), 5.91 (s, 1H); Mass forC₂₁H₃₂N₅O₄ (MH)⁺: 418, Found: 418.

White powder (28% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=7.3 Hz),1.43-1.29 (m, 2H), 1.56-1.43 (m, 2H), 2.27 (s, 3H), 2.61-2.38 (m, 6H),2.81 (t, 2H, J=8.5 Hz), 2.91 (t, 2H, J=7.6 Hz), 3.49-3.36 (m, 4H), 5.91(s, 1H); Mass for C₂₀H₂₇F₃N₅O₄ (MH)⁺: 458, Found: 458.

White powder (31% yield); ¹H NMR (DMSO): δ 0.99 (t, 3H, J=7.1 Hz), 1.05(t, 3H, J=7.3 Hz), 1.21 (t, 3H, J=7.2 Hz), 1.53-1.42 (m, 2H), 1.69-1.55(m, 4H), 2.77-2.60 (m, 8H), 3.05-2.97 (m, 2H), 3.62-3.49 (m, 4H), 5.91(s, 1H); Mass for C₂₁H₃₂N₅O₄ (MH)⁺: 418, Found: 418.

White powder (28% yield); ¹H NMR (DMSO): δ 1.03-0.81 (m, 6H), 1.42-1.30(m, 2H), 1.57-1.43 (m, 4H), 2.60-2.42 (m, 2H), 2.97-2.84 (m, 2H),3.45-3.35 (m, 4H), 3.70-3.58 (m, 4H), 5.92 (s, 1H); Mass for C₁₉H₂₇N₄O₅(MH)⁺: 391, Found: 391.

White powder (26% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=7.3 Hz), 0.98(t, 3H, J=6.9 Hz), 1.43-1.29 (m, 2H), 1.60-1.43 (m, 4H), 2.58 (t, 2H,J=8.2 Hz), 2.91 (t, 2H, J=7.9 Hz), 3.06-2.98 (m, 4H), 3.60-3.51 (m, 4H),5.92 (s, 1H), 7.30-6.95 (m, 3H); Mass for C₂₅H₃₀F₂N₅O₄ (MH)⁺: 502,Found: 502.

White powder (31% yield); ¹H NMR (CD₃OD): δ 0.99 (t, 3H, J=7.6 Hz), 1.07(t, 3H, J=7.9 Hz), 1.54-1.40 (m, 2H), 1.72-1.54 (m, 4H), 2.17 (s, 3H),2.69 (t, 2H, J=8.2 Hz), 3.06 (t, 2H, J=8.2 Hz), 3.74-3.44 (m, 8H), 5.95(s, 1H); Mass for C₂₁H₃₀N₅O₅ (MH)⁺: 432, Found: 432.

White powder (22% yield); ¹H NMR (CDCl₃): δ 1.00 (t, 3H, J=7.3 Hz), 1.07(t, 3H, J=7.9 Hz), 2.06-1.12 (m, 17H), 2.86-2.57 (m, 6H), 3.01 (t, 2H,J=7.9 Hz), 3.65-3.29 (m, 4H), 5.98 (s, 1H), 10.01-9.63 (br s, 1H); Massfor C₂₅H₃₈N₅O₄ (MH)⁺: 472, Found: 472.

White powder (29% yield); ¹H NMR (DMSO): δ 1.02-0.76 (m, 6H), 1.60-1.20(m, 8H), 1.91-1.79 (m, 2H), 2.39 (s, 3H), 2.81-2.58 (m, 4H), 2.95-2.85(m, 2H), 3.66-3.42 (m, 4H), 5.85 (s, 1H); Mass for C₂₁H₃₂N₅O₄ (MH)⁺:418, Found: 418.

White powder (42% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=7.3 Hz), 0.96(t, 3H, J=7.4 Hz), 1.40-1.30 (m, 2H), 1.58-1.44 (m, 4H), 2.58-2.50 (m,2H), 2.97-2.84 (m, 5H), 3.22-3.12 (m, 4H), 3.59-3.48 (m, 4H), 5.93 (s,1H); Mass for C₂₀H₃₀N₅O₆S (MH)⁺: 468, Found: 468.

White powder (20% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=7.5 Hz), 0.96(t, 3H, J=7.6 Hz), 1.10 (d, 3H, J=6.9 Hz), 1.56-1.32 (m, 15H), 2.67-2.41(m, 2H), 3.21-2.74 (m, 5H), 3.99-3.65 (m, 3H), 4.37-4.21 (m, 1H), 5.93(s, 1H); Mass for C₂₄H₃₆N₅O₆ (MH)⁺: 490, Found: 490.

White powder (44% yield); ¹H NMR (CD₃OD): δ 1.05 (t, 3H, J=7.5 Hz),1.70-1.53 (m, 2H), 1.93-1.81 (m, 2H), 2.37-2.22 (m, 2H), 2.46 (s, 3H),2.75-2.57 (m, 6H), 3.12-3.01 (m, 2H), 3.61-3.48 (m, 4H), 5.93 (s, 1H);Mass for C₂₀H₂₇F₃N₅O₄ (MH)⁺: 458, Found: 458.

Off-white powder (42% yield); ¹H NMR (DMSO): δ 0.97-0.90 (m, 9H),1.43-1.37 (m, 2H), 1.53-1.44 (m, 2H), 1.67-1.57 (m, 1H), 2.25 (s, 3H),2.41 (t, 4H, J=5.1 Hz), 2.55-2.51 (m, 2H), 2.93-2.88 (m, 2H), 3.39 (t,4H, J=4.8 Hz), 5.90 (s, 1H); Mass for C₂₁H₃₂N₅O₄ (MH)⁺: 418, Found: 418.

Pale yellow powder (37% yield); ¹H NMR (DMSO): δ 0.01 (m, 2H), 0.39 (m,2H), 0.70 (m, 1H), 0.95 (t, J=7.0 Hz, 3H), 1.26 (q, J=7.0 Hz, 2H), 1.49(m, 2H), 1.61 (m, 2H), 2.26 (s, 3H), 2.42 (m, 4H), 2.53 (q, J=7.5 Hz,2H), 2.92 (t, J=7.5 Hz, 2H), 3.40 (m, 4H), 5.90 (1H), δ 12.91 (s, 1H);Mass for C₂₂H₃₂N₅O₄ (MH)⁺: 430, Found: 430.

Pale yellow powder (27% yield); ¹H NMR (DMSO): δ 0.01 (m, 2H), 0.39 (m,2H), 0.70 (m, 1H), 0.95 (t, J=7.0 Hz, 3H), 1.0 (t, J=7.0 Hz, 3H), 1.26(q, J=7.0 Hz, 2H), 1.49 (m, 2H), 1.62 (m, 2H), 2.43 (q, J=7.5 Hz, 2H),2.48 (m, 4H), 2.92 (t, J=7.5 Hz, 2H), 3.40 (m, 4H), 5.90 (1H), 12.91 (s,1H); Mass for C₂₃H₃₄N₅O₄ (MH)⁺: 444, Found: 444.

Example 2 General Procedure for Preparation of Thiophene Oxime Compounds36 and 37

To a solution of thiophene (1.1 eq) in ether (ca. 0.5M concentration)was added n-BuLi/hexane (1 eq) at −78° C. under N₂ and stirred for 30min. Then nitrile (1 eq) was added and the resulting mixture was stirredovernight and allowed to warm up to room temperature. It was thenquenched with 0.5 N HCl, extracted with EtOAc, dried over Na₂SO₄,concentrated and purified by silica gel chromatography (EtOAc:hexane) toafford product 36a.

To a solution of thiophene ketone 36a (1 eq) in CH₃CN (ca. 1 Mconcentration) was added NH₂OH.HCl (1.2 eq) and NaOAc (1.2 eq) and theresulting mixture was heated at reflux overnight. It was then cooleddown to room temperature and filtered. The filtrate was concentrated togive crude product 36b as a mixture of E and Z isomers, which wereseparated by silica gel chromatography (CH₂Cl₂:MeOH) to provide pure Eand Z isomers.

To a mixture of sulfoxide 1d (1 eq) and thiophene oxime 36b (1.5 eq) inTHF/CH₃CH (1:1, ca. 0.1 M concentration) was added NaH (2.2 eq) and theresulting mixture was stirred at room temperature overnight. Then it wasquenched with sat. aqueous NH₄Cl, extracted with CH₂Cl₂, dried overNa₂SO₄, concentrated and purified by silica gel chromatography(CH₂Cl₂:MeOH) to afford Compound 36.

The following compounds were prepared using the general proceduredescribed above in Example 2, steps A-C using the appropriate startingmaterials (e.g., the appropriate nitrile and/or heterocycloalkylreagent):

White powder (18% yield); ¹H NMR (CDCl₃): δ 1.20-1.13 (m, 4H), 1.29 (t,3H, J=7.6 Hz), 2.14-2.03 (m, 1H), 3.15-3.03 (m, 2H), 6.06 (s, 1H),7.50-7.46 (m, 1H), 7.74-7.67 (m, 1H), 8.29-8.22 (m, 1H); Mass forC₁₇H₁₆N₃O₄S (MH)⁺: 358, Found: 358.

White powder (34% yield); ¹H NMR (DMSO): δ 0.98-0.91 (m, 2H), 1.20-1.08(m, 5H), 2.40-2.31 (m, 1H), 3.00-2.90 (m, 2H), 6.00 (s, 1H), 7.49-7.44(m, 1H), 7.70-7.65 (m, 1H), 8.06-8.02 (m, 1H); Mass for C₁₇H₁₆N₃O₄S(MH)⁺: 358, Found: 358.

Example 3

Pyridine (0.72 mL, 8.90 mmol) was added to the suspension of3-acetylthiophene (1.05 g, 8.33 mmol), hydroxylamine hydrochloride salt(612 mg, 8.81 mmol) in EtOH (80 mL). The resulting mixture was stirredat room temperature overnight. The volatiles were removed from thereaction mixture and the crude mixture was purified by columnchromatography (eluted with EtOAc/hexanes, 1:10) to give 38a (0.85 g,72%).

To a suspension of5-ethyl-2-methylsulfanyl-3H-pyrano[2,3-d]pyrimidine-4,7-dione (5.0 g,21.0 mmol) in DCM (250 mL), mCPBA (10.1 g, 77%, 45.2 mmol) was added.The resulting mixture was stirred at room temperature overnight. Me₂S(3.5 mL, 48 mmol) was added and stirred at room temperature for 1.5 h.Solvent was removed, and taken up with mixture of EtOAc/hexanes (1:3).Filtered, and the solid was washed with EtOAc/hexanes (1:3),extensively. The white solid was collected to give Compound 1e (2.6 g,39%).

38a (0.26 g, 1.84 mmol) was taken up with THF (6 mL) under nitrogen. NaH(46 mg, 95% oil dispersion, 1.82 mmol) was added. The resulting slurrywas stirred at room temperature for 1 h. A solution of 1e (246 mg, 0.91mmol) in DMF (2 mL) was added dropwise. The resulting mixture wasstirred at room temperature for 2 h. The reaction mixture was thenpoured into 10 mL of water, 3.5 mL of 1 N HCl and EtOAc. The solid thatprecipitated out was collected and dried to give Compound 38 (0.31 g,54%). Electrospray MS [M+1]⁺ 332.1

Example 4

38a (1.8 g) was dissolved in EtOH (35 mL), and 2 N HCl in ether (20 mL)was added. The resulting solution was stirred at room temperatureovernight. Solvent was removed, the residue was taken up with DCM andwashed with satd. Na₂CO₃ (aqueous). The organic layer was separated,dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (eluted with EtOAc/hexanes, 1:10),to give 38a (1.68 g, 93%) and 38b (0.13 g, 7%).

38b (0.13 g, 0.93 mmol) was taken up with THF (2 mL) under nitrogen. NaH(26 mg, 95% oil dispersion, 1.03 mmol) was added. The resulting slurrywas stirred at room temperature for 1 h. A solution of 1e (126 mg, 0.47mmol) in DMF (1 mL) was added dropwise. The resulting mixture wasstirred at room temperature for 2 h. The reaction mixture was thenpoured into 10 mL of water, 3.5 mL of 1 N HCl and EtOAc. The organiclayer was separated, washed with brine, dried (MgSO₄), filtered andconcentrated to give a solid. The solid was taken up with EtOAc andfiltered to give Compound 39 as a white solid (58 mg, 38%). ElectrosprayMS [M+1]⁺ 332.1

Example 5

Pyridine (0.59 mL, 7.29 mmol) was added to the suspension of2-acetylthiazole (1.05 g, 3.93 mmol), hydroxylamine hydrochloride salt(301 mg, 4.32 mmol) in THF (2 mL). The resulting mixture was stirred atroom temperature overnight. The volatile was removed and the crudemixture was purified by column chromatography (eluted with 5% EtOAc inhexanes), to give 40a, isomer A (0.2 g, 36%) and 40b, isomer B (0.21 g,37%).

The preparation of 40, isomer A and isomer B proceeded as described inthe procedure for preparing Compound 38 using 40a isomer A and 40bisomer B, respectively. MS for both: Electrospray MS [M+Na]⁺: 355.2

Compounds 41-44 were prepared using procedures of example 2, steps A-C,appropriate nitrile starting material. Compounds 45-55 were preparedusing the general procedures of Example 5, steps A and B, above, fromthe appropriate ketone:

White powder (21%); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=6.9 Hz), 1.16 (t,3H, J=7.2 Hz), 1.47-1.32 (m, 2H), 1.60-1.46 (m, 2H), 3.00-2.85 (m, 4H),6.01 (s, 1H), 7.73-7.66 (m, 1H), 7.82-7.73 (m, 1H), 8.37-8.29 (m, 1H);Mass for C₁₈H₂₀N₃O₄S (MH)⁺: 374, Found: 374.

White powder (23%); ¹H NMR (DMSO): δ 0.90 (t, 3H, J=7.3 Hz), 1.15 (t,3H, J=7.6 Hz), 1.45-1.30 (m, 2H), 1.60-1.46 (m, 2H), 2.88-2.79 (m, 2H),3.01-2.88 (m, 2H), 6.04 (s, 1H), 7.67-7.62 (m, 1H), 7.76-7.69 (m, 1H),8.48-8.41 (m, 1H); Mass for C₁₈H₂₀N₃O₄S (MH)⁺: 374, Found: 374.

Off-white powder (15% yield, mixture of E and Z isomers); ¹H NMR (DMSO):δ 1.18-1.13 (m, 3H), 3.02-2.89 (m, 2H), 6.05-5.89 (m, 1H), 8.10-7.30 (m,5H); Mass for C₂₀H₁₆N₃O₄S (MH)⁺: 394, Found: 394.

Off-white powder (23% yield); ¹H NMR (DMSO): δ 1.16 (t, 3H, J=7.3 Hz),3.03-2.87 (m, 2H), 3.33 (s, 3H), 4.55 (s, 2H), 6.03 (s, 1H), 7.76-7.68(m, 2H), 8.62-8.53 (m, 1H), 13.58-13.08 (br s, 1H); Mass for C₁₆H₁₆N₃O₅S(MH)⁺: 362, Found: 362.

Yellow powder (13%); ¹H NMR (DMSO): δ 1.14-1.02 (m, 6H), 2.96-2.83 (m,4H), 5.83 (s, 1H), 7.50-7.40 (m, 1H), 8.27-8.18 (m, 1H), 8.66-8.60 (m,1H), 9.00-8.96 (m, 1H); Mass for C₁₇H₁₇N₄O₄ (MH)⁺: 341, Found: 341.

White powder (24% yield); ¹H NMR (CDCl₃): δ 1.04 (t, 3H, J=7.3 Hz),3.09-2.83 (m, 6H), 5.50 (s, 1H), 7.35-7.24 (m, 1H), 7.50-7.36 (m, 2H),7.69 (d, 1H, J=8.8 Hz); Mass for C₁₈H₁₆N₃O₄ (MH)⁺: 338, Found: 338.

White powder (9% yield); ¹H NMR (CDCl₃): δ 1.75-1.04 (m, 15H), 2.68-2.50(m, 4H), 3.23-2.93 (m, 6H), 4.05 (d, J=13.2 Hz, 2H), 5.96 (s, 1H),7.19-7.10 (m, 2H), 7.66 (d, J=8.9 Hz, 1H), 10.19-9.72 (br s, 1H); Massfor C₂₈H₃₃N₄O₆ (MH)⁺: 521, Found: 521.

Mass for C₁₇H₁₆N₃O₄ (MH)⁺: 326, Found: 326.

Mass for C₂₂H₁₈N₃O₄ (MH)⁺: 388, Found: 388.

Mass for C₁₅H₁₄N₃O₄S (MH)⁺: 332, Found: 332.

Mass for C₁₅H₁₄N₃O₄S (MH)⁺: 332, Found: 332.

Mass for C₁₆H₁₅N₄O₄ (MH)⁺: 327, Found: 327.

Mass for C₁₆H₁₅N₄O₄ (MH)⁺: 327, Found: 327.

Mass for C₁₆H₁₅N₄O₄ (MH)⁺: 327, Found: 327.

Mass for C₁₅H₁₄N₅O₄ (MH)⁺: 328, Found: 328.

Example 6

Pyridine (0.75 mL, 9.27 mmol) was added to a suspension oftetrahydropyranone (0.50 g, 5.00 mmol) and hydroxylamine hydrochloridesalt (282 mg, 5.49 mmol) in EtOH (5 mL). The resulting mixture wasstirred at room temperature overnight. The volatiles were removed andthe crude mixture was purified by silica gel column chromatography,eluted first with 10% EtOAc/DCM then 30% EtOAc/DCM, to give 56a (0.45 g,78%) as a white solid.

Compound 56 was prepared from 56a and 1e using the procedure forpreparing Compound 38. Electrospray MS [M+1]⁺ 306.2

Compounds 57-60 were prepared using 1d and the appropriate oximestarting material, as described above in step B.

White powder (13% yield); ¹H NMR (DMSO): δ 1.86-1.70 (m, 2H), 2.41-2.21(m, 2H), 2.63-2.45 (m, 2H), 2.79-2.68 (m, 2H), 3.03-2.90 (m, 2H),3.88-3.65 (m, 4H), 6.03 (s, 1H), 13.10-12.78 (br s, 1H); Mass forC₁₆H₁₇F₃N₃O₅ (MH)⁺: 388, Found: 388.

White powder (51% yield); ¹H NMR (DMSO): δ 0.01 (m, 2H), 0.39 (m, 2H),0.70 (m, 1H), 1.26 (q, J=7.0 Hz, 2H), 1.62 (m, 2H), 2.73 (t, J=5.5 Hz,2H), 2.93 (t, J=7.5 Hz, 2H), 3.33 (m, 2H), 3.74 (t, J=5.5 Hz, 2H), 3.82(t, J=6.0 Hz, 2H), 5.98 (1H), 12.91 (s, 1H); Mass for C₁₈H₂₂N₃O₅ (MH)⁺:360, Found: 360.

White powder (33% yield); ¹H NMR (DMSO): δ 0.91 (t, 3H, J=6.4 Hz), 1.22(t, 3H, J=6.9 Hz), 1.42-1.31 (m, 2H), 1.57-1.45 (m, 3H), 1.73-1.62 (m,1H), 2.05-1.88 (m, 2H), 2.70-2.29 (m, 3H), 2.91 (t, 2H, J=8.2 Hz), 3.08(d, 1H, J=13.9 Hz), 4.16-4.07 (m, 2H), 4.46-4.31 (m, 2H), 5.98 (s, 1H);Mass for C₂₁H₂₇N₄O₆ (MH)⁺: 431, Found: 431.

The starting materials for 59 and 60 were prepared using the generalprocedure described in Example 7 (steps A-C).

White powder (51% yield); ¹H NMR (DMSO): δ 0.01 (m, 2H), 0.39 (m, 2H),0.70 (m, 1H), 1.22 (t, J=7.5 Hz, 3H), 1.24 (t, J=7.0 Hz, 2H), 1.62 (m,2H), 2.52 (t, J=5.5 Hz, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.92 (t, J=7.5 Hz,2H), 3.56 (t, J=6.0 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 4.08 (q, J=7.5 Hz,2H), 5.98 (1H), 12.91 (s, 1H); Mass for C₂₁H₂₇N₄O₆ (MH)⁺: 431, Found:431.

Compounds 61-79

Compounds 61-64 were prepared in one step from commercially availableoximes, and compounds 65-79 were prepared using a similar two-stepprocedure from the corresponding ketones, as described in thepreparation of Compound 38.

Electrospray Compound LCMS [M + 1]⁺

304.2

290.1

319.2

292.1

358.2

276.2

400.2

405.0

377.2

347.2

409.0

427.2

383.2

399.2

391.2

391.2

431.2

419.2

376.2

363.0

363.0

Example 7

4-Boc-piperidone (0.50 g, 2.51 mmol) and TFA (1.49 mL, 20.08 mmol) weredissolved in DCM (6 mL). The resulting mixture was stirred at roomtemperature for 1 h. The solvent was removed by rotary evaporation togive 0.56 g (105%) of Compound 80a as a colorless oil.

Compound 80a (440 mg, 1.13 mmol), triethylamine (0.87 mL, 6.25 mmol),ethyl isocyanate (0.27 mL, 3.39 mmol) were mixed in DCM (6 mL). Theresulting solution was stirred at room temperature overnight. Thevolatiles were removed and the residue was purified by silica gel columnchromatography (eluted with 3% NH₃-MeOH (4%) in DCM), to give 0.20 g(104%) of Compound 80b.

Pyridine (0.18 mL, 1.3 mmol) was added to the suspension of Compound 80b(0.20 g, 1.2 mmol) and hydroxylamine hydrochloride salt (0.10 g, 1.3mmol) in EtOH (5 mL). The resulting mixture was stirred at roomtemperature overnight. The volatiles were removed and the crude mixturewas purified by silica gel column chromatography (eluted with 50% EtOAcin hexanes), to give Compound 80c (0.13 g, 59%).

Compound 80c (0.13 g, 0.70 mmol) was taken up with THF (2 mL) undernitrogen. NaH (21 mg, 95% oil dispersion, 0.84 mmol) was added. Theresulting slurry was stirred at room temperature for 1 h. A solution ofCompound 1e (95 mg, 0.35 mmol) in DMF (1 mL) was added dropwise. Theresulting mixture was stirred at room temperature for 2 h. The reactionmixture was then poured into 5 mL of water, 0.83 mL of 1 N HCl, andallowed to stand at room temperature, until solid started to precipitateout. The solid was collected by filtration and washed with water, EtOAc,and CH₃CN to give 80 mg (61%) of Compound 80 as a white solid.Electrospray MS [M+1]⁺ 376.2

Compounds 81-94

Compound 81-94 were prepared in a four-step procedure from thecorresponding 4-Boc piperidone as described above in Example 7 forCompound 80, using the appropriate isocyanate, acyl chloride,chloroformate, and sulfonyl chloride.

Electrospray Compound LCMS [M + 1]⁺

390.2

373.2

361.2

389.2

389.2

403.2

387.2

401.2

405.2

417.2

383.2

409.2

465.3

477.3

Compounds 95-100

Compounds 95-100 were prepared using a four-step procedure similar tothat used to prepare Compound 80 from the appropriate N-Boc-ketones andchloroformates.

Electrospray Compound LCMS [M + 1]⁺

391.2

405.0

443.0

431.2

403.0

417.0

Example 8 Compounds 101-111

3-Fluorophenylacetic acid (10.2 g, 66.0 mmol) was dissolved in THF (200mL) and to it CDI (12.8 g, 79.2 mmol) was added. The resulting solutionwas stirred at room temperature for 1 h. MgCl₂ (6.2 g, 65.4 mmol) andmonomethyl monopotassium malonate (15.4 g, 98.3 mmol) was added. Theresulting mixture was stirred at room temperature overnight. Water wasadded and extracted with DCM, dried (MgSO₄), filtered and concentrated.The residue was purified by silica gel chromatography (eluted with 5%EtOAc in hexanes) to give Compound 101a (7.0 g, 51%) as a yellow oil.

Compound 101a (7.0 g, 33 mmol) and thiobarbituric acid (3.2 g, 22 mmol)was suspended in HOAc (33 mL), and heated in an oil bath at 120° C.overnight. The mixture was cooled to room temperature, and most of theacetic acid was removed by rotary evaporation. The residue was taken upwith water and EtOAc, and heated at 85° C. for 0.5 h, filtered, and theyellow solid was collected to give Compound 101b (3.0 g, 45%).

Compound 101b (3.0 g, 10 mmol) was suspended in DMF (40 mL) and MeI(1.32 mL, 21 mmol) was added. The resulting mixture was stirred at roomtemperature overnight. The volume of solvent was reduced to ca. 5 mL byrotary evaporation. Water and EtOAc was added and yellow solidprecipitated out. The solid was collected and washed with EtOAc to givepure Compound 101c (3.2 g, 100%).

To a suspension of Compound 101c (3.2 g, 10 mmol) in DCM (85 mL), mCPBA(4.8 g, 77%, 21.3 mmol) was added. The resulting mixture was stirred atroom temperature overnight. Me₂S (2.0 mL, 27 mmol) was added and themixture was stirred at room temperature for 1.5 h. The volume of solventwas reduced to an extent that solid started to precipitate out.Filtered, and the solid was washed with EtOAc/hexanes (1:3),extensively. The white solid was collected to give Compound 101d (1.0 g,29%).

Examples 101-112 were prepared using a procedure similar to that used toprepare Compound 61, except that Compound 101d was used instead ofCompound 1e.

Electrospray Compound LCMS [M + 1]⁺

384.2

457.3

427.2

511.3

483.0

497.3

370.2

386.2

471.3

485.0

523.3

Compound 112a was prepared using a 4-step method similar to thatdescribed for the preparation of Compound 101d, except that hexanoicacid was used instead of 3-fluorophenylacetic acid.

Compounds 112-124

Examples 112-124 were prepared using a procedure similar to thatdescribed for the preparation of Example 61, using Compound 112a insteadof Compound 1e.

Electrospray Compound LCMS [M + 1]⁺

348.2

419.0

459.0

346.2

332.2

445.2

485.0

433.2

447.0

473.3

389.2

417.2

431.0

Compound 125a was prepared using 4-step method similar to that describedfor the preparation of Compound 101d, starting with 3-thiopheneaceticacid instead of 3-fluorophenylacetic acid.

Compounds 125-128

Compounds 125-128 were prepared using a procedure similar to thatdescribed for Example 61, except that Compound 125a was used instead ofCompound 1e.

Electro- spray LCMS Compound [M + 1]⁺

372.0

374.0

415.0

358.0

Compound 129a was prepared using a 4-step procedure similar to thatdescribed for Compound 101d, except that 1-napthaleneacetic acid wasused instead of 3-fluorophenylacetic acid.

Compounds 129-131

Compounds 129-131 were prepared using a procedure similar to thatdescribed for the preparation of Compound 80 in example 7, usingCompound 129a instead of Compound 1e.

Electrospray Compound LCMS [M + 1]⁺

515.3

555.0

402.2

Compound 132a was prepared using a 3-step method similar to thatdescribed for the preparation of Compound 101d, starting fromcommercially available methyl 3-oxoheptanoate instead of3-fluorophenylacetic acid.

Compounds 132-142

Compounds 132-142 were prepared using a procedure similar to thatdescribed for the preparation of Compound 61, using Compound 132ainstead of Compound 1e.

Electrospray Compound LCMS [M + 1]⁺

332.2

334.2

405.2

375.2

437.2

360.3

433.2

491.2

419.2

318.2

304.2

Compound 143a was prepared using a 4-step sequence similar to thatdescribed for the preparation of Compound 101d, starting with3-cyclopropylpropionic acid instead of 3-fluorophenylacetic acid.

Compounds 143-145

Compounds 143-145 were prepared using a procedure similar to thatdescribed for the preparation of Compound 80 in Example 7, usingCompound 143a instead of Compound 1e.

Electrospray Compound LCMS [M + 1]⁺

346.2

417.2

445.2

Compound 146 was prepared using the procedures described in Example 5,except that 1-pyridin-4-yl-ethanone oxime was used instead of1-thiazol-2-yl-ethanone oxime.

Compounds 147 and 148 were prepared using the procedures described inExample 5, except that 1-thiazol-2-yl-propan-1-one oxime was usedinstead of 1-thiazol-2-yl-ethanone oxime.

Compound 149 was prepared using the procedures described in Example 7,except that 4-(4-fluoro-phenylmethanesulfonyl)-cyclohexanone oxime wasused instead of 4-hydroxyimino-piperidine-1-carboxylic acid ethylamide.

Compound 150 was prepared using the procedures described in Example 7,except that 4-cyclohexylmethanesulfonyl-cyclohexanone oxime was usedinstead of 4-hydroxyimino-piperidine-1-carboxylic acid ethylamide.

Compound 151 was prepared using the procedures described in Example 7,except that cyclohexanone oxime was used instead of4-hydroxyimino-piperidine-1-carboxylic acid ethylamide and Compound 129awas used instead of 1e.

Compound 152 was prepared using the procedures described in Example 1,except that cyclopropyl-(4-methyl-piperazin-1-yl)-methanone oxime wasused instead of 1-(4-methyl-piperazin-1-yl)-butan-1-one oxime and5-butyl-2-methanesulfinyl-3H-pyrano[2,3-d]pyrimidine-4,7-dione was usedinstead of 1d.

Compounds of Formula (I) wherein, for example, X is —NH— can be preparedby the method shown above.

One of skill in the art will recognize that compounds of Formula (I)wherein R² and R³ form a

group (wherein the ring shown may be unsubstituted or substituted) canbe prepared analogously to the procedure used to prepare, e.g, Compound133, except that tetrahydro-thiopyran-4-one oxime was used instead oftetrahydro-pyran-4-one oxime. The tetrahydro-thiopyran substitutedproduct can then be oxidized to the cyclic sulfoxide or sulfonederivative.

Compounds 153-285 were prepared using the various methods set forthabove in the Examples section and substituting appropriate startingmaterials, reagents and reactants. Mass spectrometry data for thesecompounds is presented below:

Electrospray Compound LCMS No. Structure [M + 1]+ 153

447.2 154

414.2 155

360.2 156

360.2 157

344.2 158

358.2 159

433.2 160

330.2 161

449.2 162

344.2 163

403.2 164

431.2 165

449.3 166

431.2 167

346.2 168

368.2 169

374.2 170

374.2 171

408.2 172

408.2 173

394.2 174

382.2 175

358.2 176

372.2 177

445.2 178

459.2 179

433.2 180

382.2 181

318.2 182

344.2 183

412.2 184

447.2 185

358.2 186

398.2 187

398.2 188

447.2 189

461.3 190

374.2 191

360.2 192

346.2 193

433.2 194

447.2 195

459.3 196

364.2 197

362.2 198

445.2 199

459.3 200

350.2 201

382.2 202

360.2 203

374.2 204

388.2 205

404.2 206

447.2 207

445.2 208

386.2 209

388.2 210

430.2 211

390.2 212

445.2 213

471.3 214

412.2 215

384.2 216

457.2 217

419.2 218

462.3 219

398.2 220

442.2 221

390.2 222

390.2 223

400.2 224

440.2 225

440.2 226

386.2 227

459.3 228

412.2 229

454.2 230

372.2 231

414.2 232

364.2 233

445.2 234

451.2 235

376.2 236

348.2 237

478.3 238

473.3 239

459.3 240

415.2 241

404.2 242

461.3 243

473.3 244

419.2 245

408.2 246

485.3 247

388.2 248

487.3 249

358.2 250

441.2 251

429.2 252

414.2 253

440.2 254

471.3 255

374.2 256

486.3 257

473.3 258

422.2 259

408.2 260

426.2 261

440.2 262

454.2 263

422.2 264

416.2 265

362.2 266

376.2 267

378.2 268

410.2 269

410.2 270

402.2 271

406.2 272

463.3 273

422.2 274

412.2 275

394.2 276

408.2 277

426.2 278

366.2 279

304.2 280

318.2 281

320.2 282

354.2 283

420.2 284

421.2 285

395.2

Determination of the Nicotinic Acid Receptor Agonist Activity of theCompounds of Formula (I)

The nicotinic acid receptor agonist activity of compounds 1-285 wasdetermined by following the inhibition of forskolin-stimulated cAMPaccumulation in cells using the MesoScale Discovery cAMP detection kitfollowing the manufacturer's protocol. Briefly, Chinese Hamster Ovary(CHO) cells expressing recombinant human nicotinic acid receptor (NAR)were harvested enzymatically, washed 1× in phosphate buffered saline(PBS) and resuspended in PBS containing 0.5 mM IBMX at 3×10⁶ cells/mL.Ten μL of cell suspension was added to each well of a 384-well platewhich contained 10 μL of test compounds. Test compounds were dilutedwith PBS containing 6 μM of forskolin. Plates were incubated for 30minutes at room temperature after the addition of cells. Lysis buffercontaining cAMP-Tag was added to each well (10 μL/well) as per themanufacturer's protocol. Plates were then incubated from 45 minutes toovernight. Prior to reading, 10 μL of read buffer was added to eachwell, and the plate was read in a Sector 6000 plate imager. The signalwas converted to cAMP concentration using a standard curve run on eachplate. Compound EC₅₀ values were determined from concentration gradientsof test compounds.

Compounds of Formula (I) of the present invention, and salts, solvates,or esters thereof, have cAMP EC₅₀ values of less than about 10,000 nM,preferably about 1000 nM or less, more preferably about 500 nM or less,even more preferably about 100 nM or less.

Using this assay, it was determined that compounds 1-285 all have cAMPEC₅₀ values of 1000 nM or less, except for Compounds 40, 55, 65, 129,130, 131, 238, 246-248, 258, 262 and 278-282 which have cAMP EC₅₀ valuesgreater than 1000 nM. Accordingly, the compounds of formula (I) can actas agonists of the nicotinic acid receptor.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof, wherein: R¹ is selected from the group consisting of H, R⁴,haloalkyl, -alkylene-R⁴, -alkylene-R⁵, -alkylene-R⁶, alkenyl, alkynyl,and -alkylene-O-alkyl; R² is selected from the group consisting ofalkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, R⁷ and -alkylene-O—R⁸; R³ isselected from the group consisting of alkyl, haloalkyl, -alkylene-R⁵,R⁴, R⁵, R⁶, and R⁷; or R² and R³ together with the carbon atom to whichthey are both attached form a cycloalkyl or heterocycloalkyl ring,wherein said cycloalkyl or heterocycloalkyl ring is unsubstituted orindependently substituted with one or more X⁵ groups, and wherein saidcycloalkyl ring can form a spirocyclic compound with a second cycloalkylring or with a heterocycloalkyl ring, wherein the second cycloalkyl ringor the heterocycloalkyl ring is unsubstituted or independentlysubstituted with one or more X⁵ groups; R⁴ is unsubstituted cycloalkylor cycloalkyl substituted with one or more X¹ groups; R⁵ isunsubstituted aryl and aryl substituted with one or more X² groups; R⁶is selected from the group consisting of unsubstituted heteroaryl andheteroaryl substituted with one or more X³ groups; R⁷ is unsubstitutedheterocycloalkyl and heterocycloalkyl substituted with one or more X⁴groups; R⁸ is selected from the group consisting of H, alkyl, R⁴, R⁵,R⁶, R⁷, —C(O)-alkyl, —C(O)—R⁵; each R⁹ is independently selected fromthe group consisting of H, alkyl, R⁴, R⁵, R⁶, and R⁷; R¹⁰ is selectedfrom the group consisting of R⁹, —C(O)-alkyl, and —C(O)—R⁵; Y is —O— or—N(R¹⁰)—; each X¹ is independently selected from the group consisting ofhalogen, alkyl, —O-alkyl, —OH, haloalkyl, aryl, and alkyne; each X² isindependently selected from the group consisting of halogen, alkyl,—O-alkyl, —OH, haloalkyl, aryl, and alkyne; each X³ is independentlyselected from the group consisting of halogen, alkyl, and N-oxide; eachX⁴ is independently selected form the group consisting of alkyl, R⁵,—C(O)-alkyl, —C(O)—R⁵, —C(O)—O-alkyl, -alkylene-R⁵, R⁴, and—S(O₂)-alkyl; and each X⁵ is independently selected from the groupconsisting of alkyl, a fused aryl ring, —C(O)-alkyl, a fused heteroarylring, —C(O)—O-alkyl, —C(O)—R⁵, —S(O₂)-alkyl, —C(O)—N(R⁹)₂, R⁵, R⁶,—C(O)—R⁴, —C(O)—O—R⁴, —S(O₂)—R⁴, —S(O₂)-alkylene-R⁴, —S(O₂)-alkylene-R⁵,—N(R⁹)—C(O)—O-alkyl, —N(R⁹)—C(O)—O—R⁴, —N(R⁹)—C(O)—N(R⁹)₂ and —N(R⁹)₂;wherein said fused aryl ring of X⁵ is unsubstituted or independentlysubstituted with one or more substitutent selected from -alkylene-R⁷ orX², and said fused heteroaryl ring of X⁵ is unsubstituted or substitutedwith one or more X³ groups.
 2. The compound of claim 1, or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,wherein: R¹ is selected from the group consisting of H, R⁴,(C₁-C₆)haloalkyl, —(C₁-C₆)alkylene-R⁴, —(C₁-C₆)alkylene-R⁵,—(C₁-C₆)alkylene-R⁶, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, and—(C₁-C₆)alkylene-O—(C₁-C₆)alkyl; R² is selected from the groupconsisting of R⁷, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —(C₁-C₆-)alkylene-R⁵,R⁴, R⁵, R⁶, R⁷ and —(C₁-C₆)alkylene-O—R⁸; R³ is selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —(C₁-C₆-)alkylene-R⁵, R⁴,R⁵, R⁶, and R⁷; or R² and R³ together with the carbon atom to which theyare both attached form a (C₃-C₁₀)cycloalkyl or (C₂-C₁₀)heterocycloalkylring, wherein said (C₃-C₁₀)cycloalkyl or (C₂-C₁₀)heterocycloalkyl ringis unsubstituted or substituted with one or more X⁵ groups. R⁴ isunsubstituted (C₃-C₁₀)cycloalkyl or (C₃-C₁₀)cycloalkyl substituted withone or more X¹ groups; R⁵ is unsubstituted (C₆-C₁₄)aryl and (C₆-C₁₄)arylsubstituted with one or more X² groups; R⁶ is selected from the groupconsisting of unsubstituted (C₂-C₁₀)heteroaryl and (C₂-C₁₀)heteroarylsubstituted with one or more X³ groups; R⁷ is unsubstituted(C₂-C₁₀)heterocycloalkyl and (C₂-C₁₀)heterocycloalkyl substituted withone or more X⁴ groups; R⁸ is selected from the group consisting of H,(C₁-C₆)alkyl, R⁴, R⁵, R⁶, R⁷, —C(O)—(C₁-C₆)alkyl, —C(O)—R⁵ each R⁹ isindependently selected from the group consisting of H, (C₁-C₆)alkyl, R⁴,R⁵, R⁶, and R⁷; R¹⁰ is selected from the group consisting of R⁹,—C(O)—(C₁-C₆)alkyl, and —C(O)—R⁵; Y is —O— or —N(R¹⁰)—; each X¹ isindependently selected from the group consisting of halogen,(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —OH, (C₁-C₆)haloalkyl, (C₆-C₁₄)aryl, and(C₁-C₆)alkyne; each X² is independently selected from the groupconsisting of halogen, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —OH,(C₁-C₆)haloalkyl, (C₆-C₁₄)aryl, and (C₁-C₆)alkyne; each X³ isindependently selected from the group consisting of halogen,(C₁-C₆)alkyl, and N-oxide; each X⁴ is independently selected form thegroup consisting of (C₁-C₆)alkyl, R⁵, —C(O)—(C₁-C₆)alkyl, —C(O)—R⁵,—C(O)—O—(C₁-C₆)alkyl, —(C₁-C₆-)alkylene-R⁵, R⁴, and —S(O₂)—(C₁-C₆)alkyl;and each X⁵ is independently selected from the group consisting of(C₁-C₆)alkyl, a fused (C₆-C₁₄)aryl ring, —C(O)—(C₁-C₆)alkyl, a fused(C₂-C₁₀)heteroaryl ring, —C(O)—O—(C₁-C₆)alkyl, —C(O)—R⁵,—S(O₂)—(C₁-C₆)alkyl, —C(O)—N(R⁹)₂, R⁵, R⁶, —C(O)—R⁴, —C(O)—O—R⁴,—S(O₂)—R⁴, —S(O₂)—(C₁-C₆)alkylene-R⁴, —S(O₂)—(C₁-C₆-)alkylene-R⁵,—N(R⁹)—C(O)—O—(C₁-C₆)alkyl, —N(R⁹)—C(O)—O—R⁴, —N(R⁹)—C(O)—N(R⁹)₂ and—N(R⁹)₂; wherein said fused (C₆-C₁₄)aryl ring of X⁵ is unsubstituted orindependently substituted with one or more substitutent selected from—(C₁-C₆)alkylene-R⁷ or X², and said fused (C₂-C₁₀)heteroaryl ring of X⁵is unsubstituted or substituted with one or more X³ groups.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate,ester, or tautomer thereof, wherein R¹ is alkyl.
 4. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, ester, ortautomer thereof, wherein R¹ is -alkylene-R⁴.
 5. The compound of claim1, or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof, wherein R¹ is -alkylene-R⁵.
 6. The compound of claim 1, or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,wherein R¹ is -alkylene-R⁶.
 7. The compound of claim 1, or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,wherein: R¹ is alkyl; and R² and R³ are each independently selected fromthe group consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, andR⁷.
 8. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester, or tautomer thereof, wherein: R¹ is haloalkyl; and R²and R³ are each independently selected from the group consisting ofalkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷.
 9. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, ester, ortautomer thereof, wherein: R¹ is -alkylene-R⁴; and R² and R³ are eachindependently selected from the group consisting of alkyl, haloalkyl,-alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷.
 10. The compound of claim 1, or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof,wherein: R¹ is -alkylene-R⁵; and R² and R³ are each independentlyselected from the group consisting of alkyl, haloalkyl, -alkylene-R⁵,R⁴, R⁵, R⁶, and R⁷.
 11. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, wherein: R¹ is-alkylene-R⁶; and R² and R³ are each independently selected from thegroup consisting of alkyl, haloalkyl, -alkylene-R⁵, R⁴, R⁵, R⁶, and R⁷.12. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester, or tautomer thereof, wherein: R¹ is alkyl; and R² and R³together with the carbon atom to which they are both attached form acycloalkyl ring, wherein said cycloalkyl ring is unsubstituted orsubstituted with one or more X¹ groups.
 13. The compound of claim 1, ora pharmaceutically acceptable salt, solvate, ester, or tautomer thereof,wherein: R¹ is alkyl; and R² and R³ together with the carbon atom towhich they are both attached form a heterocycloalkyl ring, wherein saidheterocycloalkyl ring is unsubstituted or substituted with one or moreX⁴ groups.
 14. The compound of claim 7, or a pharmaceutically acceptablesalt, solvate, ester, or tautomer thereof, wherein R¹ is —CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, or—CH₂CH₂CH₂-cyclopropyl; R² and R³ are each independently selected fromthe group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂C(CH₃)₃, —CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl, piperazinyl,piperidinyl, morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl;and R⁵ is phenyl.
 15. The compound of claim 14, or a pharmaceuticallyacceptable salt, solvate, ester, or tautomer thereof, selected from thegroup consisting of:


16. The compound of claim 13, or a pharmaceutically acceptable salt,solvate, ester, or tautomer thereof, wherein: R¹ is —CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, or —CH₂CH₂CH(CH₃)₂; and R² and R³together with the carbon atom to which they are both attached form acycloalkyl or heterocycloalkyl group selected from:

wherein each of said cycloalkyl or heterocycloalkyl rings isunsubstituted or substituted with one or more X⁴ groups.
 17. Thecompound of claim 13, or a pharmaceutically acceptable salt, solvate,ester, or tautomer thereof, selected from the group consisting of:


18. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester, or tautomer thereof, wherein R¹ is —CH₂CH₂CH₂CF₃,—CH₂CH₂—R⁴, —CH₂CH₂CH₂—R⁴, —CH₂—R⁵, or —CH₂—R⁶.
 19. The compound ofclaim 18, or a pharmaceutically acceptable salt, solvate, ester, ortautomer thereof, wherein: R² and R³ together with the carbon atom towhich they are both attached form a cycloalkyl or heterocycloalkyl groupselected from:

wherein each of said cycloalkyl or heterocycloalkyl rings isunsubstituted or substituted with one or more X⁴ groups.
 20. Thecompound of claim 19, or a pharmaceutically acceptable salt, solvate,ester, or tautomer thereof, selected from the group consisting of:


21. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester, or tautomer thereof, wherein: R¹ is —CH₂CH₂CH₂CF₃ or—CH₂CH₂—R⁴; and R² and R³ are each independently selected from the groupconsisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂C(CH₃)₃,—CH₂CH₂CF₃, —CH₂CH₂—R⁵, cyclopropyl, piperazinyl, piperidinyl,morpholinyl, phenyl, thiophenyl, pyridyl, and thiazolyl.
 22. Thecompound of claim 21, or a pharmaceutically acceptable salt, solvate,ester, or tautomer thereof, selected from the group consisting of:


23. A compound having the following structural formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 24. A compound having the following structural formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 25. A compound having the following structural formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 26. A compound having the following structural formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 27. A compound having the following structural formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 28. A compound having the following structural formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 29. A composition comprising: a compound of claim 1, or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof;and at least one pharmaceutically acceptable carrier.
 30. Thecomposition of claim 29, further comprising at least one additionaltherapeutic agent selected from the group consisting ofhydroxy-substituted azetidinone compounds, substituted β-lactamcompounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetaseinhibitors, squalene synthesis inhibitors, squalene epoxidaseinhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives,bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferaseinhibitors, cholesteryl ester transferprotein inhibitors, fish oils containing Omega 3 fatty acids, naturalwater soluble fibers, plant stanols and/or fatty acid esters of plantstanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptormodulators, LXR receptor agonists, lipoprotein synthesis inhibitors,renin angiotensin inhibitors, microsomal triglyceride transportinhibitors, bile acid reabsorption inhibitors, PPAR δ agonists,triglyceride synthesis inhibitors, squalene epoxidase inhibitors, lowdensity lipoprotein receptor inducers or activators, plateletaggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partialagonists, niacin or niacin receptor agonists, 5HT transporterinhibitors, NE transporter inhibitors, CB₁ antagonists/inverse agonists,ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1R antagonists,MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptinagonists/modulators, leptin derivatives, opioid antagonists, orexinreceptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTFderivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists,monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1agonists, phentermine, topiramate, phytopharm compound 57, ghrelinantibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroidhormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11βHSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acidtransporter inhibitors, dicarboxylate transporter inhibitors, glucosetransporter inhibitors, phosphate transporter inhibitors, antidiabeticagents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptorantagonists, apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamineagonists, melanocyte-stimulating hormone receptor analogs, melaninconcentrating hormone antagonists, leptons, galanin receptorantagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone, analogs of dehydroepiandrosterone,urocortin binding protein antagonists, glucagons-like peptide-1 receptoragonists, human agouti-related proteins (AGRP), neuromedin U receptoragonists, noradrenergic anorectic agents, appetite suppressants, hormonesensitive lipase antagonists, MSH-receptor analogs, α-glucosidaseinhibitors, apo A1 milano reverse cholesterol transport inhibitors,fatty acid binding protein inhibitors (FABP), and fatty acid transporterprotein inhibitors (FATP).
 31. The composition of claim 30, wherein saidat least one additional therapeutic agent is a HMG CoA synthetaseinhibitor selected from the group consisting of lovastatin, simvastatin,pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin,rosuvastatin calcium, and pitavastatin.
 32. The composition of claim 31,wherein said HMG CoA synthetase inhibitor is simvastatin.
 33. Thecomposition of claim 30, wherein said at least one additionaltherapeutic agent is a cholesteryl ester transfer protein inhibitor. 34.The composition of claim 33, wherein said cholesteryl ester transferprotein inhibitor is torcetrapib.
 35. A method of treating a disease,disorder, or condition comprising: administering to a patient in needthereof a therapeutically effective amount of at least one compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, ester, ortautomer thereof; wherein said disease, disorder, or condition isselected from the group consisting of metabolic syndrome, dyslipidemia,cardiovascular diseases, disorders of the peripheral and central nervoussystem, hematological diseases, cancer, inflammation, respiratorydiseases, gastroenterological diseases, diabetes, and non-alcoholicfatty liver disease.
 36. The method of claim 35, wherein said disease,disorder, or condition is dyslipidemia.
 37. The method of claim 35,further comprising administering at least one additional therapeuticagent selected from the group consisting of hydroxy-substitutedazetidinone compounds, substituted β-lactam compounds, HMG CoA reductaseinhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesisinhibitors, squalene epoxidase inhibitors, sterol biosynthesisinhibitors, nicotinic acid derivatives, bile acid sequestrants,inorganic cholesterol sequestrants, AcylCoA:CholesterolO-acyltransferase inhibitors, cholesteryl ester transfer proteininhibitors, fish oils containing Omega 3 fatty acids, natural watersoluble fibers, plant stanols and/or fatty acid esters of plant stanols,anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptormodulators, LXR receptor agonists, lipoprotein synthesis inhibitors,renin angiotensin inhibitors, microsomal triglyceride transport proteininhibitors, bile acid reabsorption inhibitors, PPAR δ agonists,triglyceride synthesis inhibitors, squalene epoxidase inhibitors, lowdensity lipoprotein receptor inducers or activators, plateletaggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partialagonists, niacin or niacin receptor agonists, 5HT transporterinhibitors, NE transporter inhibitors, CB₁ antagonists/inverse agonists,ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1R antagonists,MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptinagonists/modulators, leptin derivatives, opioid antagonists, orexinreceptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTFderivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists,monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1agonists, phentermine, topiramate, phytopharm compound 57, ghrelinantibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroidhormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11βHSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acidtransporter inhibitors, dicarboxylate transporter inhibitors, glucosetransporter inhibitors, phosphate transporter inhibitors, antidiabeticagents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptorantagonists, apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamineagonists, melanocyte-stimulating hormone receptor analogs, melaninconcentrating hormone antagonists, leptons, galanin receptorantagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone, analogs of dehydroepiandrosterone,urocortin binding protein antagonists, glucagons-like peptide-1 receptoragonists, human agouti-related proteins (AGRP), neuromedin U receptoragonists, noradrenergic anorectic agents, appetite suppressants, hormonesensitive lipase antagonists, MSH-receptor analogs, α-glucosidaseinhibitors, apo A1 milano reverse cholesterol transport inhibitors,fatty acid binding protein inhibitors (FABP), and fatty acid transporterprotein inhibitors (FATP).
 38. The method of claim 37, wherein said atleast one additional active ingredient is a HMG CoA synthetase inhibitorselected from the group consisting of lovastatin, simvastatin,pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin,rosuvastatin calcium, and pitavastatin.
 39. The method of claim 38,wherein said HMG CoA synthetase inhibitor is simvastatin.
 40. Thecompound of claim 1 having the formula:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof, wherein: R¹ is alkyl, -alkylene-cycloalkyl, haloalkyl or-alkylene-O-alkyl; R² and R³ together with the carbon atom to which theyare both attached, combine to form a monocyclic cycloalkyl, bicycliccycloalkyl or monocyclic heterocycloalkyl, wherein a monocycliccycloalkyl, bicyclic cycloalkyl or monocyclic heterocycloalkyl group isunsubstituted or optionally and independently substituted with one ormore X⁵ groups, and wherein a monocyclic cycloalkyl group may be fusedto a benzene ring, an aromatic heterocycle or a non-aromaticheterocycle, and wherein the monocyclic cycloalkyl ring can form aspirocyclic compound with a second cycloalkyl ring or with aheterocycloalkyl ring, wherein the second cycloalkyl ring or theheterocycloalkyl ring is unsubstituted or independently substituted withone or more X⁵ groups; each occurrence of X⁵ is independently alkyl,—O-alkyl, -alkylene-aryl, halo, —O—Si(R¹¹)₃, haloalkyl, —CN, —C(O)—R⁴,—C(O)—O—R⁴, —NHC(O)—O—R⁴, —S(O₂)—R⁴, or phenyl; R⁴ is alkyl orcycloalkyl, wherein the cycloalkyl group can be optionally andindependently substituted with one or more X¹ groups, and wherein thealkyl group can be optionally substituted with a cycloalkyl group; eachR¹¹ is independently alkyl or phenyl; and each occurrence of X¹ isindependently halogen, alkyl, —O-alkyl, —OH, haloalkyl, aryl or alkynyl.41. The compound of claim 40, wherein R¹ is alkyl.
 42. The compound ofclaim 40, wherein R¹ is -alkylene-cycloalkyl.
 43. The compound of claim40, wherein R¹ is alkylene-O-alkyl.
 44. The compound of claim 40,wherein R² and R³ together with the carbon atom to which they are bothattached, combine to form a monocyclic cycloalkyl.
 45. The compound ofclaim 40, wherein R² and R³ together with the carbon atom to which theyare both attached, combine to form: (i) a bicyclic cycloalkyl; or (ii) amonocyclic cycloalkyl which forms a spirocycle with a second cycloalkylgroup or with a heterocycloalkyl group.
 46. The compound of claim 40,wherein R² and R³ together with the carbon atom to which they are bothattached, combine to form a monocyclic heterocycloalkyl.
 47. Thecompound of claim 41, wherein R² and R³ together with the carbon atom towhich they are both attached, combine to form a monocyclic cycloalkyl.48. The compound of claim 41, wherein R² and R³ together with the carbonatom to which they are both attached, combine to form: (i) a bicycliccycloalkyl; or (ii) a monocyclic cycloalkyl which forms a spirocyclewith a second cycloalkyl group or with a heterocycloalkyl group.
 49. Thecompound of claim 41, wherein R² and R³ together with the carbon atom towhich they are both attached, combine to form a monocyclicheterocycloalkyl.
 50. The compound of claim 42, wherein R² and R³together with the carbon atom to which they are both attached, combineto form a monocyclic cycloalkyl.
 51. The compound of claim 42, whereinR² and R³ together with the carbon atom to which they are both attached,combine to form: (i) a bicyclic cycloalkyl; or (ii) a monocycliccycloalkyl which forms a spirocycle with a second cycloalkyl group orwith a heterocycloalkyl group.
 52. The compound of claim 42, wherein R²and R³ together with the carbon atom to which they are both attached,combine to form a monocyclic heterocycloalkyl.
 53. The compound of claim43, wherein R² and R³ together with the carbon atom to which they areboth attached, combine to form a monocyclic cycloalkyl.
 54. The compoundof claim 43, wherein R² and R³ together with the carbon atom to whichthey are both attached, combine to form: (i) a bicyclic cycloalkyl; or(ii) a monocyclic cycloalkyl which forms a spirocycle with a secondcycloalkyl group or with a heterocycloalkyl group.
 55. The compound ofclaim 43, wherein R² and R³ together with the carbon atom to which theyare both attached, combine to form a monocyclic heterocycloalkyl. 56.The compound of claim 40 having the structure:

or a pharmaceutically acceptable salt, solvate, ester, or tautomerthereof.
 57. A composition comprising: a compound of claim 40, or apharmaceutically acceptable salt, solvate, ester, or tautomer thereof;and at least one pharmaceutically acceptable carrier.
 58. Thecomposition of claim 57, further comprising at least one additionaltherapeutic agent selected from the group consisting ofhydroxy-substituted azetidinone compounds, substituted β-lactamcompounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetaseinhibitors, squalene synthesis inhibitors, squalene epoxidaseinhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives,bile acid sequestrants, inorganic cholesterol sequestrants,AcylCoA:Cholesterol O-acyltransferaseinhibitors, cholesteryl estertransfer protein inhibitors, fish oils containing Omega 3 fatty acids,natural water soluble fibers, plant stanols and/or fatty acid esters ofplant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXRreceptor modulators, LXR receptor agonists, lipoprotein synthesisinhibitors, renin angiotensin inhibitors, microsomal triglyceridetransport inhibitors, bile acid reabsorption inhibitors, PPAR δagonists, triglyceride synthesis inhibitors, squalene epoxidaseinhibitors, low density lipoprotein receptor inducers or activators,platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partialagonists, niacin or niacin receptor agonists, 5HT transporterinhibitors, NE transporter inhibitors, CB₁ antagonists/inverse agonists,ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1R antagonists,MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptinagonists/modulators, leptin derivatives, opioid antagonists, orexinreceptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTFderivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists,monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1agonists, phentermine, topiramate, phytopharm compound 57, ghrelinantibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroidhormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11βHSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acidtransporter inhibitors, dicarboxylate transporter inhibitors, glucosetransporter inhibitors, phosphate transporter inhibitors, antidiabeticagents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptorantagonists, apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamineagonists, melanocyte-stimulating hormone receptor analogs, melaninconcentrating hormone antagonists, leptons, galanin receptorantagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone, analogs of dehydroepiandrosterone,urocortin binding protein antagonists, glucagons-like peptide-1 receptoragonists, human agouti-related proteins (AGRP), neuromedin U receptoragonists, noradrenergic anorectic agents, appetite suppressants, hormonesensitive lipase antagonists, MSH-receptor analogs, α-glucosidaseinhibitors, apo A1 milano reverse cholesterol transport inhibitors,fatty acid binding protein inhibitors (FABP), and fatty acid transporterprotein inhibitors (FATP).
 59. The composition of claim 58, wherein saidat least one additional therapeutic agent is a HMG CoA synthetaseinhibitor selected from the group consisting of lovastatin, simvastatin,pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin,rosuvastatin calcium, and pitavastatin.
 60. The composition of claim 59,wherein said HMG CoA synthetase inhibitor is simvastatin.
 61. Thecomposition of claim 58, wherein said at least one additionaltherapeutic agent is a cholesteryl ester transfer protein inhibitor. 62.The composition of claim 61, wherein said cholesteryl ester transferprotein inhibitor is torcetrapib.
 63. A method of treating a disease,disorder, or condition comprising: administering to a patient in needthereof a therapeutically effective amount of at least one compound ofclaim 40, or a pharmaceutically acceptable salt, solvate, ester, ortautomer thereof; wherein said disease, disorder, or condition isselected from the group consisting of metabolic syndrome, dyslipidemia,cardiovascular diseases, disorders of the peripheral and central nervoussystem, hematological diseases, cancer, inflammation, respiratorydiseases, gastroenterological diseases, diabetes, and non-alcoholicfatty liver disease.
 64. The method of claim 63, wherein said disease,disorder, or condition is dyslipidemia.
 65. The method of claim 63,further comprising administering at least one additional therapeuticagent selected from the group consisting of hydroxy-substitutedazetidinone compounds, substituted β-lactam compounds, HMG CoA reductaseinhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesisinhibitors, squalene epoxidase inhibitors, sterol biosynthesisinhibitors, nicotinic acid derivatives, bile acid sequestrants,inorganic cholesterol sequestrants, AcylCoA:CholesterolO-acyltransferase inhibitors, cholesteryl ester transfer proteininhibitors, fish oils containing Omega 3 fatty acids, natural watersoluble fibers, plant stanols and/or fatty acid esters of plant stanols,anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptormodulators, LXR receptor agonists, lipoprotein synthesis inhibitors,renin angiotensin inhibitors, microsomal triglyceride transport proteininhibitors, bile acid reabsorption inhibitors, PPAR δ agonists,triglyceride synthesis inhibitors, squalene epoxidase inhibitors, lowdensity lipoprotein receptor inducers or activators, plateletaggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partialagonists, niacin or niacin receptor agonists, 5HT transporterinhibitors, NE transporter inhibitors, CB₁ antagonists/inverse agonists,ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1R antagonists,MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptinagonists/modulators, leptin derivatives, opioid antagonists, orexinreceptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTFderivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists,monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1agonists, phentermine, topiramate, phytopharm compound 57, ghrelinantibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroidhormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11βHSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acidtransporter inhibitors, dicarboxylate transporter inhibitors, glucosetransporter inhibitors, phosphate transporter inhibitors, antidiabeticagents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptorantagonists, apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamineagonists, melanocyte-stimulating hormone receptor analogs, melaninconcentrating hormone antagonists, leptons, galanin receptorantagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimeticagents, dehydroepiandrosterone, analogs of dehydroepiandrosterone,urocortin binding protein antagonists, glucagons-like peptide-1 receptoragonists, human agouti-related proteins (AGRP), neuromedin U receptoragonists, noradrenergic anorectic agents, appetite suppressants, hormonesensitive lipase antagonists, MSH-receptor analogs, α-glucosidaseinhibitors, apo A1 milano reverse cholesterol transport inhibitors,fatty acid binding protein inhibitors (FABP), and fatty acid transporterprotein inhibitors (FATP).
 66. The method of claim 65, wherein said atleast one additional active ingredient is a HMG CoA synthetase inhibitorselected from the group consisting of lovastatin, simvastatin,pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin,rosuvastatin calcium, and pitavastatin.
 67. The method of claim 66,wherein said HMG CoA synthetase inhibitor is simvastatin.